Novel 7-substituted 3-carboxy-oxadiazino-quinolone derivatives, their preparation and their application as anti-bacterials

ABSTRACT

A subject of the invention is the compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     in which
         either R 1  represents H, OH, NH 2 , —(CH 2 ) m —NR a R b (m=0.1 or 2),   R a  and R b  represent H, linear, branched or cyclic (C 1  -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl-(C 3 -C 6 )— alkyl, R c , S(O) 2 R c , C(O)R c , S(O) 2 R d  or C(O)R d ;   or R a  and R b  with N form an R c  radical;   R c  represents a saturated, unsaturated or 5- or 6-members aromatic ring, containing 1 to 4 heteroatoms chosen from N, O and S, optionally substituted;   R d  represents a linear, branched or cyclic (C 1 -C 6 ) alkyl, optionally substituted by 1 to 4 halogens;   or R 1  represents R c  or CHR e R c  or CHR e R d ;   R e  represents H, OH, NH 2 , NH—(C 1 -C 6 )-alk or N-(C 1 -C 6 )-alk 2 , or NH—(C 1 -C 7 )-acyl or NHR c ;   R 2  represents H, (CH 2 ) m —NR a R b , R c , CHR e R c  or CHR e R d , and R′ 2  represents H;
 
it being understood that R 1  and R 2  cannot at the same time be H or that R 1  and R 2  or R 2  and R 1  cannot be one (CH 2 ) m —NR a R b  or R c  or H and the other one OH, or one H and the other one NH 2 , or one H and the other one (CH 2 ) m —NR a R b  in which R a  and R b  represent H or alkyl or C(O)R d , in which R d  represents an unsubstituted alkyl or cycloalkyl;
   or R 1  has the above definition except H and R 2  and R′ 2  together represent gem dialkyl or alkyl-oxime, or R 2  and R′ 2  represent respectively R c  or R d  and OH, NH 2 , NHR c  or NHR f , R f  being a (C 1 -C 7 ) acyl radical;   or R 1  represents H and R 2  and R′ 2  together represent alkyl-oxime or one represents R c  and the other one represents OH, NH 2 , NHR c  or NHR f ;   n is 0 or 1;   R 3  and R′ 3  represent H or (C 1 -C 6 ) alkyl optionally substituted by 1 to 3 halogens or R 3  represents (C 1 -C 6 ) alkoxy carbonyl and R′ 3  represents H;   R4 represents methyl optionally substituted by halogen;   R 5  represents H, (C 1 -C 6 ) alkyl or (C 7 -C 12 ) arylalkyl;   R 6  represents H, fluorine, NO 2 , CF 3  or CN;   in the form of enantiomers or mixtures, as well as their salts with acids and bases;
 
their preparation and their application as anti-bacterials, in both human and veterinary medicine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to French Patent Application No. 08 01129, filed Feb. 29, 2008 and to US Provisional Application Ser. No.61/045,645, filed Apr. 17, 2008; both of which are incorporated byreference herein.

BACKGROUND AND SUMMARY

The subject of the invention is novel 7-substituted3-carboxy-oxadiazino-quinolone derivatives, their preparation and theirapplication as anti-bacterials.

7-substituted 3-carboxy-oxadiazino-quinolone derivatives have beendescribed in numerous patents, applications or publications and theremay be cited for example EP 0259804, EP 0343524, EP 0688772, U.S. Pat.No. 4,990,517, U.S. Pat. No. 5,480,879, U.S. Pat. No. 5,679,675, or alsoJ. Med. Chem 1996, 39, 3070-3088, J. Med. Chem 2002, 45, 5564-5575, orJ. Med. Chem 2004, 47, 2097-2109.

A subject of the invention is the compounds of formula (I):

in which

either R₁ represents:

H, OH, NH₂, —(CH₂)_(m)—NR_(a)R_(b) in which m=0.1 or 2,

R_(a) and R_(b) are identical or different and represent H, linear,branched or cyclic (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl-(C₁-C₆)-alkyl;

or also represent R_(c), S(O)₂R_(c), C(O)R_(c), S(O)₂R_(d) or C(O)R_(d);

or R_(a) and R_(b) form together with the nitrogen atom, an R_(c)radical;

R_(c) represents a saturated, unsaturated or aromatic 5- to 6-memberring containing 1 to 4 heteroatoms chosen from N, O and S, optionallysubstituted by 1 to 3 (C -C₆) alkyl radicals, said ring being linked, ifappropriate, to the nitrogen atom of NR_(a)R_(b) by a nitrogen atom or acarbon atom;

R_(d) represents a linear or branched (C₁-C₆) alkyl or (C₃-C₆) cyclicalkyl radical, optionally substituted by 1 to 4 halogens;

or R₁ represents R_(c) or CHR_(e)R_(c) or CHR_(e)R_(d);

R_(c) and R_(d) are as defined above, R_(e) represents H, OH, NH₂,NH—(C₁-C₆)-alk or N—(C₁-C₆)—alk₂, or NH—(C₁—C₇)-acyl or NHR_(c), R_(c)being as defined above;

R₂ represents:

H, (CH₂)_(m)—NR_(a)R_(b), R_(c), CHR_(e)R_(c) or CHR_(e)R_(d),

R_(a), R_(b), R_(c), R_(d) and R_(e) are as defined above;

and R′₂ represents H;

it being understood that R₁ and R₂ cannot at the same time be H or thatR₁ and R₂ or R₂ and R₁ cannot be one (CH₂)_(m)—NR_(a)R_(b) or R_(c) or Hand the other one OH, or one H and the other one NH₂, or one H and theother one (CH₂)_(m)—NR_(a)R_(b) in which R_(a) and R_(b) represent H or(C₁-C₆) alkyl or C(O)R_(d), in which R_(d) represents an unsubstitutedlinear or branched (C₁-C₆) alkyl or (C₃-C₆) cyclic alkyl radical;

or R₁ has the above definition except H and R₂ and R′₂ togetherrepresent gem (C₁-C₆) dialkyl or (C₁-C₆) alkyl-oxime, or R₂ and R′₂represent respectively R_(c) or R_(d) and OH, NH₂, NHR_(c) or NHR_(f),R_(c) and R_(d) being as defined above and R_(f) being a (C₁-C₇) acylradical;

or R₁ represents H and R₂ and R′₂ together represent (C₁-C₆) alkyl-oximeor one represents R_(c) and the other one represents OH, NH₂, NHR_(c) orNHR_(f), R_(c) and R_(f) being defined as above;

n is 0 or 1;

R₃ and R′₃, identical or different, represent H or (C₃-C₆) alkyloptionally substituted by 1 to 3 halogens or R₃ represents a (C₁-C₆)alkoxy carbonyl group and R′₃ represents H;

R₄ represents methyl optionally substituted by one to three halogens;

R₅ represents H, (C₁-C₆) alkyl or (C₇-C₁₂) arylalkyl;

R₆ represents H, fluorine, NO₂, CF₃ or CN;

in the form of mixtures of enantiomers or single enantiomers, as well astheir addition salts with mineral and organic acids and their salts withmineral or organic bases.

The compounds of the invention have remarkable antibacterial propertieswhich make them particularly indicated for use as medicaments in bothhuman and veterinary medicine.

In general formula (I) and hereafter:

by linear or branched (C₁-C₆) alkyl radical is meant any possibleradical and in particular methyl, ethyl, propyl or isopropyl, butyl,isobutyl or tert-butyl;

by cyclic (C₁-C₃) alkyl radical is meant cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl;

by arylalkyl radical is meant preferably benzyl or phenethyl;

by halogen is meant fluorine, chlorine, bromine or iodine, andpreferably fluorine;

by (C₁-C₇) acyl radical is meant any possible radical and in particularacetyl propionyl, butyryl or benzoyl.

When R_(c) represents a saturated ring, this is for example apyrrolidine, piperidine, piperazine or morpholine ring. When R_(c)represents an unsaturated or aromatic ring, it is for example a pyrrole,furane, thiophene, pyrazole, triazole, tetrazole, thiazole, isothiazole,thiadiazole, imidazole, isoxazole, furazane, pyridine, pyrazine,pirimidine or pyridazine ring. When R_(c) is substituted, it is inparticular by one or, if appropriate, two methyl radicals.

Among the acid salts of the products of formula (I), there may be cited,among others, of those formed with mineral acids, such as hydrochloric,hydrobromic, hydroiodic, sulphuric or phosphoric acid or with organicacids such as formic, acetic, trifluoroacetic, propionic, benzoic,maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic,aspartic, alkanesulphonic acids, such as methanesulphonic andethanesulphonic acids, arylsulphonic acids such as benzenesulphonic andparatoluenesulphonic acids. Among the alkaline salts of the products offormula (I), there may be cited, among others, those formed with mineralalkalis such as, for example, sodium, potassium, lithium, calcium,magnesium or ammonium hydroxide or organic bases such as, for example,methylamine, propylamine, trimethylamine, diethylamine, triethylamine,N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine,pyridine, piperidine, piperazine, picoline, dicyclohexylamine,morpholine, benzylamine, procaine, lysine, arginine, histidine,N-methylglucamine. A particular subject of the invention is compounds offormula (I) as defined above, in which R₃ and R′₃ represent H and R₄represents methyl, as well as those in which R₆ represents fluorine. Afurther particular subject of the invention is the compounds of formula(I) in which one of the substituents R₁ and R₂ represents(CH₂)_(m)—NR_(a)R_(b) in which m is 0 or 1, R_(c), CHR_(e)R_(c) orCHR_(e)R_(d), and the other represents H. Among these, there may becited more particularly those in which one of the substituents R₁ and R₂represents (CH₂)_(m)—NR_(a)R_(b) in which m is 0, and the otherrepresents H, and quite particularly among these latter:

those in which one of the substituents R_(a) or R_(b) represents a 5- or6-member aromatic ring, containing 1 to 4 heteroatoms chosen from N, Oand S, optionally substituted by 1 to 3 (C₁-C₆) alkyl radicals, saidring being linked, if appropriate, to the nitrogen atom of NR_(a)R_(b)by a nitrogen atom or a carbon atom, and the other represents H, and

those in which one of the substituents R_(a) or R_(b) represents aC(O)R_(d) radical and the other represents H.

A further particular subject of the invention is compounds of formula(I) as defined above, in which one of the substituents R₁ and R₂represents CHR_(e)R_(c) or CHR_(e)R_(d) and the other represents H. Afurther particular subject of the invention is compounds of formula (I)as defined above, in which R₁ represents OH or NH₂ and R₂ and R′₂represent gem (C₁-C₆) dialkyl, as well as those in which R₁ representshydrogen or —(CH₂)_(m)—NR_(a)R_(b) and R₂ and R′₂ represent (C₁-C₆)alkyl oxime. The preferred compounds of formula (I) according to theinvention are those in which n=0.

Among compounds of the invention, there may be cited the compoundsdescribed in the experimental part, in particular those whose namesfollow:

8-fluoro-3-methyl-6-oxo-9-[3-(pyrazine-2-ylaminomethyl)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-3-methyl-6-oxo-9-[(3-pyrazine-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,

8-fluoro-3-methyl-6-oxo-9-[3-(1,3,4-thiadiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,

8-fluoro-3-methyl-6-oxo-9-[(S)-3-(thiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-3methyl-6-oxo-9-[3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-3-methyl-6-oxo-9-[(R)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3.3a-diaza-phenalene-5-carboxylicacid,

9-((R,S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,9-((R)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

9-[3-(amino-thiazol-2-yl]-methyl)-pyrrolidine-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-9-[3-(Z/E)-methoxyimino)-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6-H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-9-[3-(aminomethyl)-4-methoxyimino-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,

8-fluoro-3-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

b8-fluoro-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

9-((S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

as well as their salts.

The compounds of the invention can be prepared by a method characterizedin that a compound of formula (II) is treated:

in which R₃, R′₃, R₄ and R₆ are as defined above and R′₅ has the valuesof R₅ defined above or represents another group protecting thecarboxylic function, by a compound of formula (III):

in which R₁, R₂, R′₂ and n are as previously defined, in the presence ofa base, then, if appropriate, the protective groups present areeliminated.

The procedure is carried out preferably in a sealed chamber, in solutionin the pyridine, at the reflux temperature of the latter. The base usedis preferably a tertiary amine, for example triethylamine, N-methylmorpholine or also DBU. When R′₅ represents a protective group, it canin particular be a (C₁-C₆) alkyl, a (C₂-C₆) alkenyl, or a (C₇-C₁₄)arylalkyl. After final elimination of the protective group R′₅, the acidobtained can if desired be reesterified to form a compound in which R₅is different from hydrogen. The compounds of the invention in which R₂and R′₂ represent (C₁-C₆) alkyl-oxime can also be prepared by a methodcharacterized in that a compound of formula (IV) is treated:

by an alkoxylamine or a salt of the latter.The procedure is carried out for example by action of an alkoxylaminechloride, in the presence of a base, in particular an alkaline carbonateor bicarbonate, in solution in an alkanol or in analkanol-tetrahydrofurane-water mixture.

The compound of formula (IV) can be prepared from the correspondingalcohol, for example by a Swem type oxidation reaction, in the presenceof oxalyl chloride, dimethylsulphoxide and a base, for example an aminesuch as triethylamine. Certain compounds of formula (III) are known,even commercially available, or can be prepared by methods known to aperson skilled in the art. Preparation methods are given below, as wellas in the experimental part. The compound of formula (III) in which R₁or R₂ represents a —CH₂)_(m)—NR_(a)R_(b) radical in which R_(a) and/orR_(b) represent R_(c) or R_(d) can be prepared from a compound offormula (V):

in which Pr represents a group protecting the nitrogen of the ring and mand n are as defined above, by action of a compound of formula (VI):

R_(c)-Hal or R_(d)-Hal   (VI)

in which R_(c) and R_(d) are defined as previously and Hal represents ahalogen, in the presence of a strong base, followed by deprotection ofthe nitrogen of the ring. The procedure is carried out for example inthe presence of an alkaline alkoxide, in solution in a solvent such astoluene. Hal is preferably a chlorine or a bromine.

The compound of formula (III) in which R₁ or R₂ represents a—(CH₂)_(m)—NR_(a)R_(b) radical in which R_(a) or R_(b) or R_(a) andR_(b) represent R_(c) can also be prepared from a compound of formula(VII):

in which m, n and Pr are defined as previously, by action of a compoundof formula (VIII):

R_(c)—NHP or R_(c)—NH   (VIII)

in which R_(c) and Pr are defined as previously, in the presence oftriphenylphosphine and diethyldiazadicarboxylate, in tetrahydrofurane,followed by deprotection of the nitrogen atoms. The compound of formula(III) in which R₁ or R₂ represents a —(CH₂)_(m)—Nr_(a)R_(b) radical inwhich R_(a) or R_(b) or R_(a) and R_(b) represent C(O)R_(c) or C(O)R_(d)can be prepared from a compound of formula (V) as defined above, byaction of a compound of formula (IX):

R_(c)—COOH or R_(d)—COOH   (IX)

by a peptide coupling reaction in the presence of EDCI/HOBt in solutionin a solvent such as DMF,

or by action of a corresponding acid halide or its correspondinganhydride, in the presence of a base, for example an amine such astriethylamine, in a solvent such as dichloromethane, followed bydeprotection of the nitrogen of the ring.

The compound of formula (III) in which R₁ or R₂ represents a(CH₂)_(m)—NR_(a)R_(b) radical in which R_(a) or R_(b) or R_(a) and R_(b)represent S(O)₂R_(c) or S(O)₂R_(d) can be prepared from a compound offormula (V) as defined above, by action of a correspondingalkylsulphonic acid anhydride, in the presence of a base, for example anamine such as triethylamine, in a solvent such as dichloromethane,followed by deprotection of the nitrogen of the ring. The compound offormula (III) in which R₁ or R₂ represents a —(CH₂)_(m)—NR_(a)R_(b)radical in which one of R_(a) and R_(b) represents H and the otherrepresents an R_(c) radical of 4,5-dihydro-thiazol-2-yl type can beprepared from a compound of formula (V) as defined above,

by action of the thiocarbonylimidazole, in order to obtain thecorresponding thiocyanate which is treated with 2-chloroethylamine, orits hydrochloride, in the presence of a base, for example triethylamine,followed by deprotection of the nitrogen of the ring.

The compound of formula (III) in which R₁ or R₂ represents a—(CH₂)_(m)—NR_(a)R_(b) radical in which R_(a) and R_(b) together form anR_(c) radical can be prepared either from a compound of formula (VI) asdefined above, by action of a compound H—R_(c), H being fixed to anitrogen atom of the Rc ring, in the presence of diethylazadicarboxylateand triphenylphosphine in the THF, either from a reactive derivative ofthe hydroxy of the compound of formula (VI), in particular a mesylate,by action of the same H—R_(c) compound, in the presence of sodiumhydride in DMF, followed by deprotection of the nitrogen of the ring.The compound of formula (III) in which R₁ or R₂ represents a—(CH₂)_(m)—NR_(a)R_(b) radical in which m is equal to 0 and R_(a) andR_(b) together form an R_(c) radical of [1.2,3]-triazol-1-yl type canalso be prepared from a compound of formula (X):

in which Pr and n are defined as previously,by action of the bicyclo[2,2,1]hepta-2,5-diene, followed by deprotectionof the nitrogen of the ring.

The compound of formula (III) in which R₁ or R₂ represents an R_(c)radical of 1H-tetrazole-5-yl type can also be prepared from a reagentderivative of the hydroxy of the compound of formula (VII), inparticular a mesylate, by action of the tetrabutylammonium cyanide inacetonitrile, in order to obtain the corresponding cyanide derivative,which is treated with sodium azide in the presence of a base, forexample an amine such as triethylamine, in a solvent such as toluene,followed by deprotection of the nitrogen of the ring. The compound offormula (III), if appropriate in protected form, in which R₁ representsOH or NH2 and R₂ and R′₂ represent gem dialkyl can be prepared bymethods known to a person skilled in the art and in particular by themethod described by Di Cesare et al, J Med Chem 1992, 35, (22), 4205-13.The compound of formula (III), if appropriate in protected form, inwhich R₁ represents H and R₂ and R′₂ represent respectively R_(d) andOH, NH₂ or NHR_(f), can be prepared by methods known to a person skilledin the art and in particular by the method described by Britton et al,WO0644454, or by Matsumoto et al, U.S. Pat. No. 4,649,144, or byGiordanetto et al, WO0711284, or also by Hossain et al, WO04/5295.

The compound of formula (III), if appropriate in protected form, inwhich R₁ represents H and R₂ and R′₂ represent respectively R_(c) and OHcan be prepared from the corresponding keto compound, by action of anR_(c)-Hal compound, in particular R_(c)—Br, in the presence of a strongbase, in particular butyl lithium, in solution in the tetrahydrofurane,followed if appropriate by deprotection of the nitrogen of the ring. Thecompound of formula (III) in protected form at the nitrogen of the ring,in which R₁ represents CHR_(e)R_(c) or CHR_(e)R_(d), R_(e) being an OH,can be prepared from the corresponding 2-keto compound, by action of anester-type compound of formula R_(c)COOalk or R_(d)COOalk, R_(c) andR_(d) being as defined above, in the presence of lithiumdiisopropylamide in THF, in order to obtain a compound of formula (XI):

in which R_(c), R_(d), n and Pr are as previously defined, which isreduced by potassium borohydride in methanol, in order to obtain acompound of formula (XII):

which is reduced by LiAlH₄ in the presence of aluminium chloride in THF.The compound is then deprotected at the nitrogen of the ring. A methodof this type is described in application WO2005/026154 and in theexperimental part.

The compound of formula (III) in protected form, in which R₁ representsCHR_(e)C_(c) or CHR_(e)R_(d), R_(c) being an OH, can also be preparedfrom the compound of formula (XIII):

in which Pr and n are as previously defined,by action of oxalyl chloride in DMSO in the presence of a base such astriethylamine, in order to obtain a compound of formula (XIV):

in which n and Pr are as previously defined,which is treated with a compound of R_(c)-Hal or R_(d)-Hal type, Halbeing in particular a bromine, in the presence of a base such as butyllithium. The compound is then deprotected. A method of this type isdescribed in application WO2005/026154 and further in the experimentalpart.

The compound of formula (III) in protected form, in which R₁ representsCHR_(e)R_(c) or CHR_(e)R_(d), R_(e) being a NH₂ or NHR_(f), can beprepared from the compound obtained above, the OH function of which isactivated by action of methanesulphonyl chloride in the presence of abase, for example triethylamine, within dichloromethane, then treatedwith sodium azide in DMF, in order to obtain the compound of formula(XV):

which is reduced by hydrogen in the presence of palladium over carbonwith an alkanol. The compound is isolated in protected form regardingthe nitrogen of the ring. The compound is then deprotected. A method ofthis type is described in patent EP 1182202 and further in theexperimental part.

Protection of the heterocyclic nitrogen and the amines is carried out inparticular, according to circumstances, in the form of benzyle ortrityle derivatives, in the form of carbamates, in particular allyl,benzyl, phenyl or tertbutyl, or also in the form of silyl derivativessuch as dimethyl, trimethyl, triphenyl tertbutyl or also diphenyltertbutyl-silyl derivatives. Deprotection is carried out, according tothe nature of the protective group, by sodium or lithium in liquidammonia, by hydrogenolysis or using soluble palladium 0 complexes, byaction of an acid, or by action of tetrabutylammonium fluoride or strongbases such as sodium hydride or potassium tert-butylate. These reactionsare well known to a person skilled in the art and examples are givenhereafter in the experimental part. The compound of formula (II) isgenerally known and can be prepared by the methods described in U.S.Pat. No. 4,801,584.

The compound of formula (II) in which R₃ and/or R′₃ represent/s an alkylradical optionally substituted by 1 to 3 halogens can be prepared from acompound of formula (II) in which R₃ and R′₃ represent a hydrogen, whichis hot-treated with an alkaline aqueous base then neutralized, in orderto obtain the compound of formula (XVI):

in which R₄, R′₅ and R₆ are defined as above, which is treated indioxane at boiling point by a compound of formula (XVII)

in which R₃ and R′₃ are defined as above.

The compound of formula (II) in which R₄ represents a methyl radicalsubstituted by 1 to 3 halogens can be prepared according to a method ofthe type described in U.S. Pat. No. 4,801,584. As stated above, thecompounds of formula (I) can be in the form of enantiomers or mixturesof enantiomers essentially at position 9 of the ring. The compounds offormula (I) are obtained without racemization and as a resultenantiomers can be obtained by using the corresponding enantiomer of thecompound of formula (III) or (IV). The compounds according to theinvention have remarkable antibacterial properties and these propertiesmanifest themselves over a wide spectrum of gram (−) bacteria, but alsoa wide spectrum of gram (+). This balanced antibacterial activitydistinguishes them from the similar compounds of the prior art, forexample marbofloxacine or also ofloxacine, and means that they areparticularly indicated for use as medicaments in human medicine, butalso in veterinary medicine for which there is a need for compoundswhich are particularly active in relation to these bacteria. Thus thecompounds are active in particular on gram (+) bacteria such asStreptococcus uberis or Staphylococcus aureus, but also Mycoplasma bovisor bovirhinis, or Clostridium perfringens or Enterococcus faecalis,while still being remarkably active on gram (−) bacteria such asMannheimia haemolytica, Bordetella bronchiseptica, Escherichia coli orPseudomonas aeruginosa. These properties make said products, as well astheir salts with pharmaceutically acceptable acids and bases, suitablefor use as medicaments in the treatment of conditions with susceptiblegerms and in particular those involving staphylococci, such asstaphylococcal septicaemia, malignant staphylococcal infection of theface or skin, pyoderma, septic or suppurating sores, anthrax, phlegmon,erysipeles, primitive or post-influenzal acute staphylococcalinfections, bronchial pneumonia, pulmonary suppurations.

These products can also be used as medicaments in the treatment ofcolibacilloses and associated infections, in Proteus, Klebsiella,Pseudomonas or also Salmonella infections and in other conditions causedby gram (−) bacteria. A further subject of the present invention istherefore, as medicaments and in particular antibiotic medicaments, theproducts of formula (I) as defined above as well as their salts withpharmaceutically acceptable acids and bases.

More particularly, a subject of the invention is, as medicaments, thepreferred products of formula (I) mentioned above, in particularincluding the compounds whose names follow:

8-fluoro-3-methyl-6-oxo-9-[3-(pyrazine-2-ylaminomethyl)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-3-methyl-6-oxo-9-(3-pyrazine-2-ylamino)-pyrrolidine-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-3-methyl-6-oxo-9-[3-(1,3,4-thiadiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-3-methyl-6-oxo-9-[(S)-3-(thiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-3methyl-6-oxo-9-(3-(2.2,2-trifluoro-acetylamino)-pyrrolidine-1-yl)-2,3-dihydro-6H-1-oxa-3.3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-3-methyl-6-oxo-9-((R)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl(-2,3-dihydro-6H-1-oxa-3.3a-diaza-phenalene-5-carboxylicacid,

9-((R,S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

9-((R)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3.3a-diaza-phenalene-5-carboxylicacid,

9-(3-(amino-thiazol-2-yl]-methyl)-pyrrolidine-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-9-[3-((Z/E)-methoxyimino)-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6-H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-9-[3-(aminomethyl)-4-methoxyimino-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-3-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

8-fluoro-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,

9-((S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-oxa-3,3a-diaza-phenalene-5-carboxylic acid, as well as their salts.

A subject of the invention is also the pharmaceutical compositionscontaining, as active ingredient, at least one of the medicamentsaccording to the invention as defined above.

These compositions can be administered by oral, rectal, parenteral, inparticular intramuscular route, by respiratory route or by local routein topical application to the skin and mucous membranes. Thecompositions according to the invention can be solid or liquid and bepresent in the pharmaceutical forms commonly used in human medicine,such as for example, plain or sugar-coated tablets, gelatin capsules,granules, suppositories, injectable preparations, ointments, creams,gels; they are prepared according to the customary methods. The activeingredient/s can be incorporated in same, using excipients which arecustomarily used in these pharmaceutical compositions, such as talc, gumarabic, lactose, starch, magnesium stearate, cocoa butter, aqueous ornon-aqueous vehicles, fatty substances of animal or vegetable origin,paraffin derivatives, glycols, various wetting agents, dispersants oremulsifiers, preservatives. These compositions can in particular bepresent in the form of a powder intended to be dissolvedextemporaneously in an appropriate vehicle, for example, non-pyrogenicsterile water. The dose administered varies according to the conditiontreated, the patient in question, the administration route and theproduct envisaged. It can, for example, be comprised between 0.25 g and10 g per day, by oral route in humans, with the product described inExample 1 or also comprised between 0.25 g and 10 g per day byintramuscular or intravenous route.

DETAILED DESCRIPTION

The following examples illustrate the invention. In the followingexamples and, if applicable, in the description above, the abbreviationsof chemical names have the following meanings:

-   EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,-   HOBt: 1-hydroxybenzotriazole,-   DBU: 1,8-diaza-bicyclo-[5,4,0]-undec-7-ene,-   TNOC:    8,9-difluoro-3-methyl-6-oxo-2,3,3a,6-tetrahydronaphtho-[1,8-de][1.3]oxazine-5-carboxylic    acid,-   ACN: acetonitrile,-   THF: tetrahydrofurane,-   DMF: dimethylformamide,-   LiHMDS: lithium-hexamethyldisilylazide,-   DMAP: dimethylaminopyridine,-   TFA: trifluroacetic acid,-   Boc: tert-butoxycarbonyl,-   CBz: benzyloxycarbonyl-   MS: mass spectrum,-   ESI⁺: positive ion electrospray ionization.-   NMR: The spectra were determined on spectrometers of the 300 or 400    MHz type, the proton and carbon spectra being respectively recorded    at 300 and 75 MHz or 400 and 100 MHz, in solution in CDCl₃, or    DMSO-d₆, MeOH-d₄. The values recorded are expressed in δ (ppm) and    represent the s, d, t, quad, dd and m values. The constant JAB is    expressed in Hz. Unless otherwise indicated, the reactions are    carried out under dry inert gas and at ambient temperature.

“General method A” (coupling) consists of reacting the product “TNOC”(1.0 equivalent) and the aminated derivative in suspension in pyridine(0.2M) in a sealed chamber overnight at 120° C. under stirring. Thesolvent is evaporated off and toluene and/or methanol are added. Afterconcentration to dryness, the crude product is triturated in methanoland separated then dried.

“General method B” (Boc deprotection) consists of adding a large excessof TFA to a solution in dichloromethane at 0° C. of protected aminoderivative (N-Boc). The reaction is carried out at ambient temperatureand followed by chromatography over silica. The solution is concentratedto dryness and toluene and/or methanol are added. The crude product isobtained in the form of a trifluoroacetate.

“General method C” (peptide coupling) consists of adding 1.2 to 2.0equivalents of EDCI and 1.2 to 2.0 equivalents of HOBt or DMAP and 1.2to 2.0 equivalents of heteroaryl carboxylic acid, at 0° C., to a 0.2 to0.6M solution within DMF of protected amino(piperidine) derivative N-Bocor N-CBz. The mixture is maintained under stirring at ambienttemperature for 16 to 18 hours, then diluted with ethyl acetate andwashed with water. The solution is then dried and concentrated todryness under reduced pressure, then the residue is purified bychromatography over silica eluting with the cyclohexane-ethyl acetatemixture.

EXAMPLE 1 Preparation of8-fluoro-3-methyl-6-oxo-9-[3-(pyrazin-2-ylaminomethyl)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (5a)

Step A: Preparation of 3a and 3b

In a sealed tube, 40 mL of dry toluene was degazed with Argon during 15minutes, palladium acetate (165 mg, 0.24 mmol, 0.04 eq.) andracemic-2,2′-bis(diphenylphosphino)-,1′-binaphthyl (152 mg, 0.24 mmol,0.04 eq.) were added and the mixture was degazed with Argon for 10minutes. Then 2-chloropyrazine (700 mg, 6.11 mmol, 1.0 eq.),3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g,7.33 mmol, 1.2 eq.) and sodium tert-butoxide (822 mg, 8.55 mmol, 1.4eq.) were added and the mixture was stirred at 70° C. overnight. Thereaction was concentrated in vacuum. The resulting crude product waspurified by flash chromatography on silica gel, eluting withcyclohexane-ethyl acetate (1:1 to 0:1) to afford a mixture of 3a and 3b(900 mg, 2:1, over yield 38%).

Step B: Preparation of 4a and 4b

The mixture of 3a and 3b (900 mg) was dissolved in dichloromethane (25mL) and trifluoroacetic acid (3 mL) was added. The mixture was stirredat room temperature for 6 hours. The reaction was concentrated in vacuumand co-evaporated with toluene and methanol. The residue was purified byflash chromatography on silica gel, eluting with dichloromethane—7N NH₃methanol (gradient from 5% to 100% of 7N NH₃ methanol) 4a and 4b wereseparated during the flash chromatography purification to affordquantitatively 4a and 4b as colorless oils.

4a: MS (ESI⁺) (+0.1% HCOOH): 179.21 [C₉H₁₄N₄+H]⁺ (m/z)

4b: MS (ESI⁺) (+0.1% HCOOH): 257.14 [C₁₃H₁₆N₆+H]⁺ (m/z)

Step C: Preparation of8-fluoro-3-methyl-6-oxo-9-[3-(pyrazin-2-ylaminomethyl)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diazaphenalene-5-carboxylicacid (5a) In a sealed tube,8,9-difluoro-3-methyl-6-oxo-2,3,3a,6-tetrahydronaphto[1,8-de][1,3]oxazine-5-carboxylicacid—TNOC -(200 mg, 0.71 mmol, 1.0 eq.) and 4a (447 mg, 2.51 mmol, 3.53eq.) were suspended in 3 mL of dry pyridine and 1 mL ofN-methylmorpholine. The reaction mixture was stirred at 120° C. for 16hours. The reaction was cooled to room temperature and the precipitatewas filtered. The precipitate was triturated with dichloromethane andmethanol and then evaporated. The residue was sonicated in ethanol,refluxed and then filtrated to afford the title compound as a yellowsolid (275 mg, 74%)

HPLC (gradient 20% to 80% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 441.2 [C₂₁H₂₁FN₆O₄+H]⁺ (m/z)

mp=238-240° C.

EXAMPLE 29-{3-[di-(pyrazin-2-yl-amino)-methyl]pyrrolidin-1-yl}8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (5b)

The compound 5b was obtained from TNOC (180 mg, 1.0 eq.) 4b (330 mg,1.29 mmol, 2.02 eq.) following the procedure described for thepreparation of 5a. The mixture was evaporated and co-evaporated withtoluene, sonicated with ethanol, refluxed and filtrated to afford thetitle compound as a yellow solid (145 mg, 43%).

HPLC (gradient 20% to 80% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 519.0 [C₂₅H₂₃FN₈O₄+H]⁺ (m/z)

mp=213-215° C.

EXAMPLE 39-{3-[di-(pyridin-2-yl-amino)-methyl]pyrrolidin-1-yl}8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (5c)

Step A: Preparation of 3c

Utilizing the procedure described for the preparation of 3b exceptsubstituting 2-chloropyrazine for 2-chloropyridine (4.4 mmol). Theresulting crude product was purified by flash chromatography on silicagel, eluting with cyclohexane-ethyl acetate (1:1 to 2:8) the titlecompound was obtained as a colorless oil (0.5 g, 32%).

Step B: Preparation of 4c

3c (1.4 g, 3.9 mmol) was dissolved in dichloromethane (40 mL) and 4N HClin dioxane (10 mL) was added. The mixture was stirred at roomtemperature for 4 hours. The reaction was concentrated in vacuum. Theresidue was purified by flash chromatography on silica gel, eluting withdichloromethane—7N NH₃ in methanol (gradient from 5% to 20% of 7N NH₃ inmethanol). The title compound was obtained as colorless oil (0.7 g,70%).

MS (ESI⁺) (+0.1% HCOOH): 255.15 [C₁₅H₁₈N₄+H]⁺ (m/z)

Step C:9-{3-[di-pyridin-2-yl-amino)-methyl]pyrrolidin-1-yl}8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (5c)

The compound 5c was obtained from TNOC (259 mg, 0.92 mmol, 1.0 eq.) and4c (700 mg, 2.76 mmol, 3.0 eq.) in 5 mL of pyridine andN-methyhnorpholine (0.2 mL, 1.84 mmol, 2.0 eq.) following the sameprocedure described for 5b. The mixture was evaporated, the residue wastriturated in water and the precipitate was filtrated. The solid wastriturated with methanol and filtrated. The crude residue was purifiedby preparative TLC purification eluting with dichloromethane and 5% ofmethanol to afford the title compound as a yellow solid (249 mg, 52%)

HPLC (gradient 5% to 80% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 517.14 [C₂₇H₂₅FN₆O₄+H]⁺ (m/z)

mp=199° C.

EXAMPLE 48-Fluoro-3-methyl-6-oxo-9-[3-(thiazol-2-ylaminomethyl)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (10a)

Step A: Preparation of 8a

To a 0° C. solution of the commercially available3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester 6 (1.5 g,7.19 mmol, 1.2 eq. prepared according WO2007/21982) in dry THF (25 mL),triphenylphosphine (2.4 g, 8.98 mmol, 1.5 eq.) was added. After completedissolution, diethylazodicarboxylate −40% w/v in toluene-(4 mL, 8.98mmmol, 1.5 eq.) was added dropwise followed by thiazol-2-yl-carbamicacid tert-butyl ester 7a (1.2 g, 5.99 mmol, 1.0 eq.). The mixture wasstirred at room temperature for 18 hours. The reaction was evaporatedunder reduced pressure. The resulting crude product was purified byflash chromatography on silica gel, eluting with cyclohexane-ethylacetate (9:1 to 8:2) to afford 8a as a colorless gum (1.95 g, 85%)

Tetrahedron letters 1995, 36, 36, 6463-6566

Step B: Preparation of 9a

8a (1.95 g, 5.08 mmol, 1.0 eq.) was dissolved in ethyl acetate (10 mL)and 4N HCl in dioxane (10 mL) was added. The mixture was stirred at roomtemperature for 6 hours. The reaction was concentrated in vacuum. Theresidue was purified by flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 10% methanol) thendichloromethane—7N NH₃ in methanol (gradient from 4% to 70% of 7N NH₃ inmethanol). The title compound was obtained as a colorless oil (915 mg,95%).

MS (ESI⁺) (+0.1% HCOOH): 184.23 [C₈H₁₃N₃S+H]⁺ (m/z)

Step C:8-Fluoro-3-methyl-6-oxo-9-[3-(thiazol-2-ylaminomethyl)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (10a)

Following the procedure described for the preparation of 5a, 10a wasobtained from TNOC (450 mg, 1.59, 1.0 eq.) and 9a (915 mg, 5.0 mmol, 3.1eq.) to afford the title compound as a yellow solid (421 mg, 60%). Ananalytical sample was obtained by preparative TLC purification elutingwith dichloromethane—methanol (gradient from 2.5% to 5% of methanol).

HPLC (gradient 5% to 80% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 446.1 [C₂₀H₂₀FN₅O₄S+H]⁺ (m/z)

mp=268-270° C.

EXAMPLE 58-Fluoro-3-methyl-9-{3-[(5-methyl-[1,3,4]oxadiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (10b)

Step A: Preparation of 7b

5-Methyl-[1,3,4]oxadiazol-2-ylamine (500 mg, 5.04 mmol, 1.0 eq.) wasdissolved in 5 mL of dry pyridine and di-tert-butyl dicarbonate (1.1 g,5.04 mmol, 1.0 eq.) was added, the mixture was stirred at 70° C. for 16hours. The reaction was evaporated and co-evaporated with toluene. Theresulting crude product was purified by flash chromatography on silicagel, eluting with cyclohexane-ethyl acetate (9:1 to 0:1) to afford 7b(513 mg, 51%) as a white solid.

Step B: Preparation of 8b

Compound 8b was obtained following the procedure described in thepreparation of 8a except substituting 7a for 7b. The resulting crudeproduct was purified by flash chromatography on silica gel, eluting withcyclohexane-ethyl acetate (9:1 to 1:1) to afford 8b as sticky oil (1.7g, contaminated with Mitsunobu reagents).

Step C: Preparation of 9b

Utilizing the procedure described in the preparation of 4a-4b exceptsubstituting 3a-3b for 8b, the title compound was obtained as acolorless oil (180 mg, 21%).

MS (ESI⁺) (+0.1% HCOOH): 183.27 [C₈H₁₄N₄+H]⁺ (m/z)

Step D:8-Fluoro-3-methyl-9-{3-[(5-methyl-[1,3,4]oxadiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (10b)

Utilizing the procedure for the preparation of 5b, 10b was obtained withTNOC (140 mg, 0.49 mmol, 1.0 eq.) and 9b (180 mg, 0.98 mmol, 2.0 eq.).An analytical sample was obtained by preparative TLC purificationeluting with dichloromethane—methanol (gradient from 2.5% to 5% ofmethanol) to afford the title compound as a yellow solid (76 mg, 34%).

HPLC (gradient 5% to 80% ACN in H₂O): >95% MS (ESI⁺) (+0.1% HCOOH):446.9 [C₂₀H₂₁FN₆O₅+H]⁺ (m/z)

mp=240° C.

EXAMPLE68-Fluoro-9-(3-{[furan-2-carbonyl)-amino]methyl}-pyrrolidin-1-yl)-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (13)

Step A: Preparation of 11

To a 0° C. solution of furan-2-carboxylic acid (1.1 g, 9.81 mmol, 1.3eq.) in dry DMF (20 mL) were added EDC (1.88 g, 9.81 mmol, 1.3 eq.) andHOBt (1.32 g, 9.81 mmol, 1.3 eq.). The mixture was stirred at roomtemperature for 20 minutes and 1 (1.1 g, 9.81 mmol, 1.0 eq.) was added.The reaction was stirred at room temperature for 16 hours. The mixturewas diluted with ethyl acetate and washed first with water and then witha saturated aqueous NaHCO₃ solution, the organic extracts were driedover anhydrous magnesium sulphate and were evaporated under reducedpressure. The resulting crude product was purified by flashchromatography on silica gel, eluting with cyclohexane-ethyl acetate(8:2 to 1:1) to afford 11 (1.8 g, 81%) as a colorless gum.

Step B: Preparation of 12

Utilizing the procedure described in preparation of 4a-4b exceptsubstituting 3a-3b for 11, the title compound was obtained as acolorless oil (1.0 g, 85%).

MS (ESI⁺) (+0.1% HCOOH): 195.19 [C₁₀H₁₄N₂O₂+H]⁺ (m/z)

Step C:8-Fluoro-9-(3-{[furan-2-carbonyl)-amino]methyl}-pyrrolidin-1-yl)-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (13)

Utilizing the procedure for the preparation of 5a, 13 was obtained fromTNOC (520 mg, 1.84 mmol, 1.0 eq.) and 12 (1.0 g, 5.55 mmol, 3.0 eq.).The mixture was evaporated and co-evaporated with toluene, sonicatedwith methanol, refluxed and filtrated to afford the title compound as ayellow solid (645 mg, 78%).

HPLC (gradient 5% to 80% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 457.1 [C₂₂H₂₁FN₄O₆+H]⁺ (m/z)

mp=278-280° C.

EXAMPLE 78-fluoro-3-methyl-6-oxo-9-[3-pyrazin-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6-H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (17)

Step A: Preparation of 15

Utilizing the procedure described in preparation of 3a-3b exceptsubstituting 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butylester for 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester 14{Alegria, 2004 #20}, the title compound was obtained as a colorless oil(800 mg, 69%).

Step B: Preparation of 16

Utilizing the procedure described in preparation of 4c exceptsubstituting 3c for 15; the residue was purified by flash chromatographyon silica gel, eluting with dichloromethane—7N NH₃ in methanol (gradientfrom 5% to 20% of 7N NH₃ in methanol) to afford the title compound wasobtained as a colorless oil (500 mg, quantitative).

MS (ESI⁺) (+0.1% HCOOH): 165.18 [C₈H₁₂N₄+H]⁺ (m/z)

Step C:8-fluoro-3-methyl-6-oxo-9-[3-pyrazin-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6-H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (17)

Utilizing the procedure described in preparation of 5c exceptsubstituting 4c for 16 (500 mg, 3.05 mmol, 3.0 eq.), the title compoundwas obtained as a yellow solid (175 mg, 41%).

HPLC (gradient 5% to 80% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 427.15 [C₂₀H₁₉FN₆O₄+H]⁺ (m/z)

mp=269° C., dec.

EXAMPLE 88-fluoro-3-methyl-6-oxo-9-[3-pyridin-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (22)

Step A: Preparation of 20

To a −78° C. solution of 2-fluoropyridine (1.0 mL, 11.29 mmol, 1.0 eq.)and 1-benzyl-pyrrolidin-3-ylamine (2.0 g, 11.29 mmol, 1.0 eq.) in dryTHF (5 mL) was added LiHMDS IM in THF (23 mL, 22.57 mmol, 2.0 eq.). Thereaction was stirred at room temperature for 1 hour and then at 90° C.overnight. The reaction was diluted with water and extracted with ethylacetate; the organic extracts were dried over anhydrous magnesiumsulphate and were evaporated under reduced pressure. The resulting crudeproduct was purified by flash chromatography on silica gel, eluting with100% ethyl acetate to afford 20 (2.08 g, 72%) as a colorless gum.

MS (ESI⁺) (+0.1% HCOOH): 254.06 [C₁₆H₁₉N₃+H]⁺ (m/z)

Step B: Preparation of 21

To a solution of 20 (2.08 g, 8.22 mmol) in methanol (25 mL) were added 2drops of trifluoroacetic acid and Pd/C (500 mg). The mixture wassubmitted to hydrogenation at atmospheric pressure and at 40° C. for 36hours. The reaction was filtered over Celite® and evaporated underreduced pressure. The residue was purified by flash chromatography onsilica gel, eluting with dichloromethane—methanol (gradient from 5% to10% methanol) then dichloromethane—7N NH₃ in methanol (gradient from 10%to 20% of 7N NH₃ in methanol). The title compound was obtained as anorange oil (1.3 g, 97%).

MS (ESI⁺) (+0.1% HCOOH): 164.16 [C₉H₁₃N₃+H]⁺ (m/z)

Step C:8-fluoro-3-methyl-6-oxo-9-[3-pyridin-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (22)

Utilizing the procedure described in the preparation of 5a exceptsubstituting 4a for 21 (1.3 g, 7.96 mmol, 3.2 eq.), the title compoundwas obtained as a yellow solid (900 mg, 85%).

HPLC (gradient 20% to 80% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 426.1 [C₂₁H₂₀FN₅O₄+H]⁺ (m/z)

mp=278-280° C.

EXAMPLE 98-Fluoro-3-methyl-9-[3-(5-methyl-[1,3,4]oxadiazol-2-ylamino)-pyrrolidin-1-yl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (24d)

Step A: Preparation of 24b

Utilizing the procedure described in preparation of 8b exceptsubstituting 6 for 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (1.1 g, 5.87 mmol) 23{Hansen, 2003 #1}. The resulting crudeproduct was purified by flash chromatography on silica gel, eluting withcyclohexane-ethyl acetate (9:1 to 1:1) to afford 24b as sticky oil (2.5g, contaminated with Mitsunobu reagents).

Step B: Preparation of 24c

Utilizing the procedure described in preparation of 4a-4b exceptsubstituting 3a-3b for 24b, the title compound was obtained as acolorless oil (200 mg, 20%).

MS (ESI⁺) (+0.1% HCOOH): 169.24 [C₇H₁₂N₄O+H]⁺ (m/z)

Srep C:8-Fluoro-3-methyl-9-[3-(5-methyl-[1,3,4]oxadiazol-2-ylamino)-pyrrolidin-1-yl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (24d)

Utilizing the procedure for the preparation of 10b except substituting9b for 24c (200 mg, 1.19 mmol, 2.0 eq.). The precipitate was filteredand washed with water then diethyl ether to afford the title compound asa yellow solid (62 mg, 25%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 431.2 [C₁₉H₁₉FN₆O₅+H]⁺ (m/z)

mp=285° C.

EXAMPLE 108-Fluoro-3-methyl-6-oxo-9-[3-([1,3,4]thiadiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-]-oxa-3,3a-diaza-phenalene-5-carboxylicacid (25d)

Step A: Preparation of 25b

Utilizing the procedure described in preparation of 8a exceptsubstituting 6 for 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (1.88 g, 10.0 mmol, 1.0 eq.) 23 {Hansen, 2003 #1} and 7a for25a{Gravestock, 2003 #2}(1.62 g, 8.06 mmol, 0.8 eq.). The resultingcrude product was purified by flash chromatography on silica gel,eluting with cyclohexane-ethyl acetate (9:1 to 8:2) to afford 25b assticky oil (1.63 g, 54%).

Step B: Preparation of 25c

Utilizing the procedure described in preparation of 4a-4b exceptsubstituting 3a-3b for 25b (2.7 g, 7.29 mmol). The residue was purifiedby flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 10% methanol) thendichloromethane—7N NH₃ in methanol (gradient from 10% to 40% of 7N NH₃in methanol). The title compound was obtained as a colorless oil (951mg, 76%).

Step C:8-Fluoro-3-methyl-6-oxo-9-[3-([1,3,4]thiadiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (25d)

Utilizing the procedure for the preparation of 5a except substituting 4afor 25c (950 mg, 5.59 mmol, 3.0 eq.). The precipitate was filtered andwashed with water; the residue was triturated in hot methanol and gaveafter filtration the title compound as a yellow solid (688 mg, 73%).

HPLC (gradient 5% to 95% ACN in H₂O): >90%

MS (ESI⁺) (+0.1% HCOOH): 433.1 [C₁₈H₁₇FN₆O₄S+H]⁺ (m/z)

mp=320° C., dec.

EXAMPLE 118-Fluoro-3-methyl-6-oxo-9-[3-([1,2,4]thiadiazol-5-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (26d).

Step A: Preparation of 26b

Utilizing the procedure described in preparation of 8a exceptsubstituting 6 for 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (1.2 g, 6.41 mmol, 1.0 eq.) 23 {Hansen, 2003 #1} and 7a for 26a{Gravestock, 2003 #2}(1.03 g, 5.13 mmol, 0.8 eq.). The resulting crudeproduct was purified by flash chromatography on silica gel, eluting withcyclohexane-ethyl acetate (9:1 to 8:2) to afford 26b as sticky oil (2.03g, 85%).

Step B: Preparation of 26c

Utilizing the procedure described in preparation of 4a-4b exceptsubstituting 3a-3b for 26b (2.0 g, 5.40 mmol). The residue was purifiedby flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 20% methanol) thendichloromethane—7N NH₃ in methanol (gradient from 5% to 40% of 7N NH₃ inmethanol). The title compound was obtained as a colorless oil (1.0 g,quantitative).

Step C:8-Fluoro-3-methyl-6-oxo-9-[3-([1,2,4]thiadiazol-5-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (26d)

Utilizing the procedure for the preparation of 25d except substituting25c for 26c (1.0 g, 5.88 mmol, 2.5 eq.). The residue was triturated withhot methanol and filtrated. The title compound was obtained as a yellowsolid (614 mg, 61%).

HPLC (gradient 5% to 95%% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 433.2 [C₁₈H₁₇FN₆O₄S+H]⁺ (m/z)

mp=285° C., dec.

EXAMPLE 129-[3-(4,5-Dimethyl-thiazol-2-ylamino)-pyrrolidin-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (27d)

Step A: Preparation of 27a

Utilizing the procedure for the preparation of 7a except substituting2-aminothiazole for 2-amino-4,5-dimethylthiazole hydrochloride (2.5 g,15.2 mmol, 1.0 eq.). The title compound was obtained as a white solid(1.07g, 31%).

Step B: Preparation of 27b

Utilizing the procedure described in preparation of 8a exceptsubstituting 6 for 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (1.1 g, 5.83 mmol, 1.0 eq.) 23{Hansen, 2003 #1} and 7a for 27a(1.07 g, 4.67 mmol, 0.8 eq.). The resulting crude product was purifiedby flash chromatography on silica gel, eluting with cyclohexane-ethylacetate (1:0 to 8:2) to afford 27b as a colorless oil (1.45 g, 78%).

Step C: Preparation of 27c

Utilizing the procedure described in preparation of 4c exceptsubstituting 3c for 27b (1.45 g, 3.65 mmol) with 15 mL of 4N HCl indioxane. The residue was purified by flash chromatography on silica gel,eluting with dichloromethane—7N NH₃ in methanol (gradient from 5% to 20%of 7N NH₃ in methanol). The title compound was obtained as a colorlessoil (940 mg, quantitative).

MS (ESI⁺) (+0.1% HCOOH): 198.21 [C₉H₁₅N₃S+H]⁺ (m/z)

Step D:9-[3-(4,5-Dimethyl-thiazol-2-ylamino)-pyrrolidin-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (27d)

Utilizing the procedure described in preparation of 5c exceptsubstituting 4c for 27c (940 mg, 4.76 mmol, 4.0 eq.). The reaction wasevaporated under reduced pressure; the residue was triturated with waterand filtrated. The resulting solid was triturated and filtrated firstwith methanol, then with dichloromethane, and finally with methanol; thetitle compound was obtained as a yellow solid (143 mg, 26%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 460.4 [C₂₁H₂₂FN₅O₄S+H]⁺ (m/z)

mp=266° C., dec.

EXAMPLE 13

8-Fluoro-3-methyl-9-[3-(4-methyl-thiazol-2-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (28d)

Step A: Preparation of 28b

Utilizing the procedure described in the preparation of 8a exceptsubstituting 6 for 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (1.1 g, 5.83 mmol, 1.0 eq.) 23 {Hansen, 2003 #1} and 7a for 28a{Hadida Ruah, 2007 #3}(1.0 g, 4.67 mmol, 0.8 eq.). The resulting crudeproduct was purified by flash chromatography on silica gel, eluting withcyclohexane-ethyl acetate (1:0 to 8:2) to afford 28b as a colorless oil(1.45 g, 87%).

Step B: Preparation of 28c

Utilizing the procedure described in the preparation of 4c exceptsubstituting 3c for 28b (1.55 g, 4.04 mmol) with 7 mL of 4N HCl indioxane. The residue was purified by flash chromatography on silica gel,eluting with dichloromethane—7N NH₃ in methanol (gradient from 5% to 10%of 7N NH₃ in methanol). The title compound was obtained as a white solid(1.0 g, quantitative).

MS (ESI⁺) (+0.1% HCOOH): 184.15 [C₈H₁₃N₃S+H]⁺ (m/z)

Step C:8-Fluoro-3-methyl-9-[3-(4-methyl-thiazol-2-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (28d)

Utilizing the procedure described in the preparation of 5c exceptsubstituting 4c for 28c (1.0 g, 5.46 mmol, 4.0 eq.). The reaction wasevaporated under reduced pressure; the residue was triturated with waterand filtrated. An analytical sample was obtained by preparative TLCpurification eluting with dichloromethane—methanol (gradient from 2.5%to 5% of methanol) to afford the title compound as a yellow solid (100mg, 33%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 446.2 [C₂₀H₂₀FN₅O₄S+H]⁺ (m/z)

mp=260° C., dec.

EXAMPLE 148-Fluoro-3-methyl-9-[3-(5-methyl-thiazol-2-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (29d)

Step A: Preparation of 29a

Utilizing the procedure for the preparation of 7a except substituting2-aminothiazole for 2-amino-5-methylthiazole (2.0 g, 17.5 mmol, 1.0eq.), the title compound was obtained as a white solid (1.07 g, 45%).

Step B: Preparation of 29b

Utilizing the procedure described in the preparation of 8a exceptsubstituting 6 for 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (1.86 g, 9.92 mmol, 1.0 eq.) 23{Hansen, 2003 #1} and 7a for 29a(1.7 g, 7.93 mmol, 0.8 eq.). The resulting crude product was purified byflash chromatography on silica gel, eluting with cyclohexane-ethylacetate (1:0 to 1:1) to afford 29b as a yellow oil (2.1 g, 69%).

Step C: Preparation of 29c

Utilizing the procedure described in the preparation of 4c exceptsubstituting 3c for 29b (2.1 g, 5.48 mmol, 1.0 eq.) with 15 mL of 4N HClin dioxane. The residue was purified by flash chromatography on silicagel, eluting with dichloromethane—7N NH₃ in methanol (gradient from 5%to 20% of 7N NH₃ in methanol). The title compound was obtained as awhite solid (930 mg, 93%).

MS (ESI⁺) (+0.1% HCOOH): 184.15 [C₈H₁₃N₃S+H]⁺ (m/z)

Step D:8-Fluoro-3-methyl-9-[3-(5-methyl-thiazol-2-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (29d)

Utilizing the procedure described in the preparation of 5c exceptsubstituting 4c for 29c (930 mg, 5.13 mmol, 4.0 eq.). The reaction wasevaporated under reduced pressure; the residue was triturated with waterand filtrated. An analytical sample was obtained by preparative TLCpurification eluting with dichloromethane—methanol (gradient from 2.5%to 5% of methanol) to afford the title compound as a yellow solid (72mg, 25%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 446.1 [C₂₀H₂₀FN₅O₄S+H]⁺ (m/z)

mp=265° C., dec.

EXAMPLE 158-Fluoro-3-methyl-9-[3-(3-methyl-isothiazol-5-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (30d)

Step A: Preparation of 30b

Utilizing the procedure described in the preparation of 8a exceptsubstituting 6 for 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (1.7 g, 9.08 mmol, 1.0 eq.) 23{Hansen, 2003 #1} and 7a for30a{Butira, 2004 #4} (1.94 g, 9.08 mmol, 1.0 eq.). The resulting crudeproduct was purified by flash chromatography on silica gel, eluting withcyclohexane-ethyl acetate (9:1 to 7:3) to afford 30b as a yellow oil(2.9 g, 84%).

Step B: Preparation of 30c

Utilizing the procedure described in the preparation of 4a-4b exceptsubstituting 3a-3b for 30b (2.9 g, 7.57 mmol, 1.0 eq.). The residue waspurified by flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 10% methanol) thendichloromethane—7N NH₃ in methanol (gradient from 10% to 30% of 7N NH₃in methanol). The title compound was obtained as a colorless oil (1.0 g,72%).

Step B:8-Fluoro-3-methyl-9-[3-(3-methyl-isothiazol-5-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (30d)

Utilizing the procedure for the preparation of 10b except substituting9b for 30c (1.0 g, 5.46 mmol, 3.0 eq.). The reaction was evaporatedunder reduced pressure; the residue was triturated with ethanol andfiltrated (251 mg). An analytical sample was obtained by preparative TLCpurification eluting with dichloromethane—methanol (gradient from 2.5%to 7.5% of methanol) to afford the title compound as a yellow solid (42mg, 10%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH) : 446.26 [C₂₀H₂₀FN₅O₆S+H]⁺ (m/z)

Mp=265° C.

EXAMPLE 168-Fluoro-3-methyl-9-[3-(3-methyl-isoxazol-5-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (31d)

Step A: Preparation of 31b

Utilizing the procedure described in the preparation of 8a exceptsubstituting 6 for 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (0.47 g, 2.52 mmol, 1.0 eq.) 23 {Hansen, 2003 #1} and 7a for31a{Gravestock, 2003 #2} (0.4 g, 2.02 mmol, 0.8 eq.). The resultingcrude product was purified by flash chromatography on silica gel,eluting with cyclohexane-ethyl acetate (95:5 to 6:4) to afford 31b as awhite solid (0.5 g, 67%).

Step B: Preparation of 31c

Utilizing the procedure described in the preparation of 4c exceptsubstituting 3c for 31b (0.6 g, 1.63 mmol, 1.0 eq.) with 10 mL of 4N HClin dioxane. The residue was purified by flash chromatography on silicagel, eluting with dichloromethane—7N NH₃ in methanol (gradient from 5%to 20% of 7N NH₃ in methanol). The title compound was obtained as awhite solid (230 mg, 84%).

MS (ESI⁺) (+0.1% HCOOH): 168.43 [C₈H₁₃N₃O+H]⁺ (m/z)

Step C:8-Fluoro-3-methyl-9-[3-(3-methyl-isoxazol-5-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (31d)

Utilizing the procedure described in the preparation of 5c exceptsubstituting 4c for 31 c (230 mg, 1.38 mmol, 2.0 eq.). The reaction wasevaporated under reduced pressure; the residue was triturated with waterand filtrated. An analytical sample was obtained by preparative TLCpurification eluting with dichloromethane—methanol (gradient from 2.5%to 5% of methanol) to afford the title compound as a yellow solid (50mg, 17%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 430.2 [C₂₀H₂₀FN₅O₅+H]⁺ (m/z)

mp=244° C., dec.

EXAMPLE 178-Fluoro-3-methyl-9-[3-(5-methyl-isoxazol-3-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (32d)

Step A: Preparation of 32b

Utilizing the procedure described in the preparation of 8a exceptsubstituting 6 for 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (4.25 g, 22.7 mmol, 1.0 eq.) 23 {Hansen, 2003 #1} and 7a for 32a{almansa Rosales, 2006 #5} (3.6 g, 18.2 mmol, 0.8 eq.). The resultingcru product was purified by flash chromatography on silica gel, elutingwith cyclohexane-ethyl acetate (1:0 to 8:2) to afford 32b as a colorlessoil (1.8 g, 27%).

Step B: Preparation of 32c

Utilizing the procedure described in the preparation of 4c exceptsubstituting 3c for 32b (1.8 g, 4.9 mmol, 1.0 eq.) with 10 mL of 4N HClin dioxane. The residue was purified by flash chromatography on silicagel, eluting with dichloromethane—7N NH₃ in methanol (gradient from 5%to 20% of 7N NH₃ in methanol). The title compound was obtained as awhite solid (1.0 g, quantitative).

MS (ESI⁺) (+0.1% HCOOH): 168.22 [C₈H₁₃N₃O+H]⁺ (m/z)

Step C:8-Fluoro-3-methyl-9-[3-(5-methyl-isoxazol-3-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (32d)

Utilizing the procedure described in the preparation of 5c exceptsubstituting 4c for 32c (1.0 g, 5.98 mmol, 4.0 eq.). The reaction wasevaporated under reduced pressure; the residue was triturated first withethanol and filtrated and secondly with methanol to afford the titlecompound as a yellow solid (532 mg, 83%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 430.25 [C₂₀H₂₀FN₅O₅+H]⁺ (m/z) mp=263° C., dec.

EXAMPLE 188-Fluoro-3-methyl-6-oxo-9-[(S)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (36a)

Step A: Preparation of 34a

Utilizing the procedure described in the preparation of 8a exceptsubstituting 6 for (R)-3-hydroxy-pyrrolidine-1-carboxylic acidtert-butyl ester 33a (1.0 g, 5.34 mmol, 1.1 eq.) and 7a (1.17 g, 5.87mmol, 1.0 eq.). The resulting crude product was purified by flashchromatography on silica gel, eluting with cyclohexane-ethyl acetate(95:5 to 85:15) to afford 34a as a colorless oil (1.8 g, 97%).

Step B: Preparation of 35a

Utilizing the procedure described in preparation of 4c exceptsubstituting 3c for 34a (1.8 g, 4.87 mmol, 1.0 eq.) and dichloromethanefor ethyl acetate with 20 mL of 4N HCl in dioxane. The reaction wasstirred one hour at 60° C. and evaporated under reduced pressure. Theresidue was purified by flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 10% methanol) thendichloromethane—7N NH₃ in methanol (gradient from 20% to 50% of 7N NH₃in methanol). The title compound was obtained as a white solid (780 mg,94%).

MS (ESI⁺) (+0.1% HCOOH): 170.15 [C₇H₁₁N₃S+H]⁺ (m/z)

Step C:8-Fluoro-3-methyl-6-oxo-9-[(S)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (36a)

Utilizing the procedure for the preparation of 10b except substituting9b for 35a (780 mg, 4.61 mmol, 3.0 eq.). The reaction was evaporatedunder reduced pressure; the residue was triturated with methanol andfiltrated (462 mg). An analytical sample was obtained by preparative TLCpurification eluting with dichloromethane—methanol (gradient from 2.5%to 5% of methanol) to afford the title compound as a yellow solid (30mg, 17%).

HPLC (gradient 5% to 80% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 432.18 [C₁₉H₁₈FN₅O₄S+H]⁺ (m/z)

mp=275° C.° C.

EXAMPLE 198-Fluoro-3-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (36b)

Step A: Preparation of 34b

Utilizing the procedure described in the preparation of 8a exceptsubstituting 6 for (S)-3-hydroxy-pyrrolidine-1-carboxylic acidtert-butyl ester 33b (1.0 g, 5.34 mmol, 1.0 eq.) and 7a (1.07 g, 5.34mmol, 1.0 eq.). The resulting crude product was purified by flashchromatography on silica gel, eluting with cyclohexane-ethyl acetate(1:0 to 8:2) to afford 34b as an colorless oil (1.8 g, quantitative).

¹H NMR (CDCl₃): δ 7.60 (d, 1H, J=3.7), 7.02 (d, 1H, J=3.6), 5.73-5.62(m, 1H), 3.40-3.31 (m, 1H), 3.74-3.67 (m, 3H), 2.52-2.39 (m, 1H),2.22-2.13 (m, 1H), 1.57 (s, 9H), 1.46 (s, 9H).

Step B: Preparation of 35b

Utilizing the procedure described in the preparation of 4c exceptsubstituting 3c for 34b (1.8 g, 4.87 mmol) with 15 mL of 4N HCl indioxane. The residue was purified by flash chromatography on silica gel,eluting with dichloromethane—7N NH₃ in methanol (gradient from 5% to 20%of 7N NH₃ in methanol). The title compound was obtained as a white solid(900 mg, quantitative).

MS (ESI⁺) (+0.1% HCOOH): 170.17 [C₇H₁₁N₃S+H]⁺ (m/z)

Step C:8-Fluoro-3-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (36b)

Utilizing the procedure described in the preparation of 5c exceptsubstituting 4c for 35b (900 mg, 5.32 mmol, 4.0 eq.). The reaction wasevaporated under reduced pressure; the residue was triturated with waterand filtrated. The resulting residue was triturated with methanol andfiltrated to afford the title compound as a yellow solid (440 mg, 77%)

HPLC (gradient 5% to 80% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 432.12 [C₁₉H₁₈FN₅O₄S+H]⁺ (m/z)

mp=245-250° C.° C., dec.

EXAMPLE 209-[3-(4,5-Dihydro-thiazol-2-ylamino)-pyrrolidin-1-yl]-8-fluoro-3-methyl--oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (40)

Step A: Preparation of 37

To a −78° C. solution of 14 (1.5 g, 8.05 mmol, 1.0 eq.) in drydichloromethane (40 mL), thiocarbonylimidazole (1.81 g, 9.66 mmol, 1.2eq.) was added. The mixture was then allowed to reach slowly roomtemperature overnight. The reaction mixture_was washed with water, theorganic extracts were dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The residue was purified by flash chromatographyon silica gel, eluting with cyclohexane-ethyl acetate (9:1 to 7:3) toafford 37 as a colorless oil (1.29 g, 70%).

Step B: Preparation of 38

To a solution of 37 (1.87 g, 8.19 mmol, 1.0 q.) in dry THF (30 mL) wereadded triethylamine (2.3 mL, 16.38 mmol, 2.0 eq.) and 2-chloroethylaminehydrochloride (1.14 g, 9.33 mmol, 1.14 eq.). After 18 hours at roomtemperature the reaction mixture was refluxed for one day. After coolingthe salts were filtrated and the filtrate was evaporated under reducedpressure. The residue was purified by flash chromatography on silicagel, eluting with 100% ethyl acetate then with dichloromethane—methanol(gradient from 5% to 15% of methanol) to afford 38 as an colorless oil(1.9 g, 85%).

Step C: Preparation of 39

Utilizing the procedure described in preparation of 4a-4b exceptsubstituting 3a-3b for 38 (1.9 g, 7.00 mmol). The residue was purifiedby flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 10% methanol) thendichloromethane—7N NH₃ in methanol (gradient from 10% to 30% of 7N NH₃in methanol). The title compound was obtained as a colorless oil (0.5 g,42%).

Step D:9-[3-(4,5-Dihydro-thiazol-2-ylamino)-pyrrolidin-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (40)

Utilizing the procedure for the preparation of 10b except substituting9b for 39 (500 mg, 2.92 mmol, 2.7 eq.). The reaction was filtrated (125mg). An analytical sample was obtained by preparative TLC purificationeluting with dichloromethane—methanol (gradient from 2.5% to 5% ofmethanol) to afford the title compound as a light yellow solid (30 mg,6.5%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 434.0 [C₁₉H₂₀FN₅O₄S+H]⁺ (m/z)

mp=265-267° C.° C., dec.

EXAMPLE 218-fluoro-3-methyl-6-oxo-9-[3-([1,2,4]triazolo-1-yl)-pyrrolidine]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid and8-fluoro-3-methyl-6-oxo-9-[3-([1,3,4]triazolo-1-yl)-pyrrolidine-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (44a-44b)

Step A: Preparation of 42a-42b

Prepared according to the procedure reported in US2003/0225107 exceptsubstituting 5(R)-3-[4-(1-cyanocyclopropan-1-yl]-5-hydroxymethyloxazolidin-2-one for 23 (1.6 g, 8.54 mmol, 1.0 eq.),tetramethylazodicarboxamide for diethylazodicarboxylate, butylphosphinefor triphenylphosphine and benzene for tetrahydrofurane. The resultingcrude product was purified by flash chromatography on silica gel,eluting with cyclohexane-ethyl acetate (7:3 to 0:1) to afford 42a-42b asa colorless oil (845 mg, 42%).

Step B: Preparation of 43a-43b

Utilizing the procedure described in PREPARATION of 4a-4b exceptsubstituting 3a-3b for 42a-42b (950 mg, 3.98 mmol). The residue waspurified by flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 10% methanol) thendichloromethane—7N NH₃ in methanol (gradient from 10% to 30% of 7N NH₃in methanol). 43a-43b was obtained as a light yellow oil (555 mg,quantitative).

MS (ESI⁺) (+0.1% HCOOH): 139.22 [C₆H₁₀N₄+H]⁺ (m/z)

Step C:8-fluoro-3-methyl-6-oxo-9-[3-([1,2,4]triazolo-1-yl)-pyrrolidine]-2,3-dihydro-3,3a-diaza-phenalene-5-carboxylicacid and8-fluoro-3-methyl-6-oxo-9-[3-([1,3,4]triazolo-pyrrolidine-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (44a-44b)

The title compound was prepared utilizing the procedure for thepreparation of 5a except substituting 4a for 43a-43b (555 mg, 4.02 mmol,2.8 eq.). The precipitate was filtered and washed with water; theresidue was triturated in hot methanol and gave after filtration thetitle compound as a yellow solid (371 mg, 65%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (EST+) (+0.1% HCOOH): 401.2 [C₁₈H₁₇FN₆O₄+H]⁺ (m/z)

mp=277-279° C.

EXAMPLE 228-fluoro-3-methyl-6-oxo-9-[3-([1,2,3]triazolo-1-yl)-pyrrolidine]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid and 8-fluoro-3-methyl-6-oxo-9-[3-([1,2, 5]triazolo-1-yl)-pyrrolidine-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid(49a-49b)

Step A: Preparation of 47a-47b

The title compound was prepared according to the procedure reported inUS2003/0225107 except substituting5(R)-3-[4-(1-cyanocyclopropan-1-yl]-5-methanesulfonyloxymethyloxazolidin-2-onefor 45 {Genevois-Borella, 2005 #21}(1.6 g, 8.53 mmol, 1.0 eq.). Theresulting crude product was purified by flash chromatography on silicagel, eluting with cyclohexane-ethyl acetate (1:0 to 1:1) to afford47a-47b as a white solid (1.4 g, 69%).

Step B: Preparation of 48a-48b

Utilizing the procedure described in the preparation of 4c exceptsubstituting 3c for 47a-47b (1.9 g, 7.97 mmol, 1.0 eq.) with 10 mL of 4NHCl in dioxane. The residue was purified by flash chromatography onsilica gel, eluting with dichloromethane—7N NH₃ in methanol (gradientfrom 0% to 1 0% of 7N NH₃ in methanol). The title compound was obtainedas a white solid (807 mg, 73%).

MS (ESI⁺) (+0.1% HCOOH): 139.05 [C₆H₁₀N₄+H]⁺ (m/z)

Step C:8-fluoro-3-methyl-6-oxo-9-[3-([1,2,3]triazolo-1-yl)-pyrrolidine]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid and8-fluoro-3-methyl-6-oxo-9-[3-([1,2,5]triazolo-1-yl)-pyrrolidine-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (49a-49b)

Utilizing the procedure described in the preparation of 5c exceptsubstituting 4c for 48a-48b (800 mg, 5.79 mmol, 3.0 eq.). The reactionwas poured in ethanol; the precipitate was filtrated and washed withmethanol to afford the title compound as a yellow solid (641 mg, 83%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 400.99 [C₁₈H₁₇FN₆O₄+H]⁺ (m/z)

mp=278-279° C.° C., dec.

EXAMPLE 238-Fluoro-3-methyl-6-oxo-9-(3-[1,2,3]triazol-1-yl-pyrrolidin-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (49a) Step A: Preparation of 47a

The title compound was prepared according to the procedure reported inUS2003/0225107 except substituting5(R)-azidomethyl-3-[4-(1-cyanocyclopropan-1-yl)phenyl]oxazolidin-2-onefor 50 (EP1500643, 1.5 g, 7.07 mmol, 1.0 eq.). The reaction mixture wasevaporated under reduced pressure to afford 47a as a yellow oil (1.7 g,quantitative).

Step B: Preparation of 48a

Utilizing the procedure described in PREPARATION of 4c exceptsubstituting 3c for 47a (1.7 g, 7.07 mmol) with 10 mL of 4N HCl indioxane. The residue was purified by flash chromatography on silica gel,eluting with dichloromethane—7N NH₃ in methanol (gradient from 0% to 5%of 7N NH₃ in methanol). The title compound was obtained as a white solid(900 mg, 92%).

Step C:8-Fluoro-3-methyl-6-oxo-9-(3-[1,2,3]triazol-1-yl-pyrrolidin-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (49a)

Utilizing the procedure described in PREPARATION of 5c exceptsubstituting 4c for 48a (1.03 g, 7.45 mmol, 4.0 eq.). The reaction waspoured in ethanol, the precipitate was filtrated and washed withmethanol to afford the title compound as a yellow solid (580 mg, 78%)

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 401.19 [C₁₈H₁₇FN₆O₄+H]⁺ (m/z)

mp=264° C., dec.

EXAMPLE 248-Fluoro-3-methyl-6-oxo-9-[3-(1H-tetrazol-5-yl)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (54)

Step A: Preparation of 51

To a solution of 45 (4.66 g, 18.7 mmol, 1.0 eq.) in acetonitrile (10 mL)was added tetrabutylammonium cyanide (10.0 g, 37.4 mmol, 2.0 eq.), thereaction mixture was stirred at 65° C. overnight. After cooling themixture was diluted with ethyl acetate and washed with a saturatedaqueous NaHCO₃ solution. The organic extracts were dried over anhydroussodium sulphate and evaporated under reduced pressure. The resultingcrude product was purified by flash chromatography on silica gel,eluting with cyclohexane-ethyl acetate (1:0 to 1:1) to afford 51 as ayellow oil (2.9 g, 79%).

Step B: Preparation of 52

To a solution of 51 (1.0 g, 5.1 mmol, 1.0 eq.) in toluene (10 mL) wereadded sodium azide (0.497 g, 7.64 mmol, 1.5 eq.) and triethylaminehydrochloride, the reaction mixture was stirred at 100° C. for 24 hours.After cooling the mixture was diluted with ethyl acetate and washed withwater. The organic extracts were dried over anhydrous sodium sulphateand evaporated under reduced pressure. The resulting crude product waspurified by flash chromatography on silica gel, eluting withdichloromethane and 5% of methanol to afford the title compound as ayellow oil (1.0 g, 82%).

Step C: Preparation of 53

Utilizing the procedure described in the preparation of 4c exceptsubstituting 3c for 52 (1.09 g, 4.56 mmol, 1.0 eq.) with 10 mL of 4N HClin dioxane. The residue was triturated with dichloromethane andfiltrated. The resulting solid was triturated in 7N NH₃ methanol andevaporated under reduced pressure. The title compound was obtained as abeige solid (780 mg, quantitative).

Step D:8-Fluoro-3-methyl-6-oxo-9-[3-(1H-tetrazol-5-yl)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (54)

Utilizing the procedure described in the preparation of 5c exceptsubstituting 4c for 53 (780 mg, 5.61 mmol, 4.0 eq.). The reaction waspoured in ethanol, the precipitate was filtrated. The residue wastriturated and filtrated firstly with water, secondly with methanol andat last with dichloromethane to afford the title compound as a yellowsolid (60 mg, 11 %)

HPLC (gradient 5% to 95% CAN in H₂O): >90%

MS (ESI⁺) (+0.1% HCOOH) : 402.28 [C₁₇H₁₆PN₇O₄+H]⁺ (m/z)

mp=250° C., dec.

EXAMPLE 258-Fluoro-9-{3-[(furan-2-carbonyl)-amino]-pyrrolidin-1-yl}-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (5 7a)

Step A: Preparation of 55a

Utilizing the procedure described in the preparation of 11 exceptsubstituting 1 for 14 (1.0 g, 4.97 mmol, 1.0 eq.), the resulting crudeproduct was purified by flash chromatography on silica gel, eluting withcyclohexane-ethyl acetate (8:2 to 0:1) to afford 55a (1.29 g, 92%) as awhite solid.

Step B: Preparation of 56a

Utilizing the procedure described in the preparation of 4c exceptsubstituting 3c for 55a (1.29 g, 4.60 mmol, 1.0 eq.) with 10 mL of 4NHCl in isopropanol and dichloromethane for ethyl acetate. The residuewas purified by flash chromatography on silica gel, eluting withdichloromethane—10% methanol then dichloromethane—7N NH₃ in methanol(gradient from 0% to 10% of 7N NH₃ in methanol). The title compound wasobtained as a white gum (725 mg, 87%).

MS (ESI⁺) (+0.1% HCOOH): 181.33 [C₉H₁₂N₂O₂+H]⁺ (m/z)

Step C:8-Fluoro-9-{3-[(furan-2-carbonyl)-amino]-pyrrolidin-1-yl}-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (57a)

Utilising the procedure for the preparation of 5a, except substituting4a for 56a (725 mg, 4.02 mmol, 3.0 eq.), after cooling the reaction wasfiltered. The crude solid was triturated with boiling ethanol andfiltrated to afford the title compound as a beige solid (497 mg, 84%).

HPLC (gradient 5% to 80% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 443.1 [C₂₁H₁₉FN₄O₆+H]⁺ (m/z)

mp=306-308° C.

EXAMPLE 268-Fluoro-3-methyl-6-oxo-9-[3-(3,3,3-trifluoro-propionylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (57c)

Step A: Preparation of 55c

Utilizing the procedure for the preparation of 55b, except substitutingcyclopentanecarbonylchloride for 3,3,3-trifluoro-propionyl chloride (2.3g, 15.30 mmol, 1.5 eq.), the resulting crude product was purified byflash chromatography on silica gel, eluting with cyclohexane-ethylacetate (8:2 to 1:1) to afford 55c (1.4 g, 46%) as a pale yellow oil.

Step B: Preparation of 56c

Utilizing the procedure described in the preparation of 4a-4b exceptsubstituting 3a-3b for 50c (1.4 g, 4.72 mmol, 1.0 eq.). The residue waspurified by flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 15% methanol) 56c (TFAsalt) was obtained as a light yellow oil (1.4 g, quantitative).

MS (ESI⁺) (+0.1% HCOOH): 197.13 [C₇H₁₁F₃N₂O+H]⁺ (m/z)

Step C:8-Fluoro-3-methyl-6-oxo-9-[3-(3,3,3-trifluoro-propionylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (57c)

Utilizing the procedure for the preparation of 5a, except substituting4a for 56c (1.4 g, 4.51 mmol, 4.0 eq.), was evaporated under reducedpressure The crude solid was triturated with methanol and filtrated thenthe precipitate was triturated with boiling methanol and filtrated toafford the title compound as a yellow solid (277 mg, 57%).

HPLC (gradient 5% to 95% ACN in H₂O): >90%

MS (ESI⁺) (+0.1% HCOOH): 459.0 [C₁₉H₁₈F₄N₄O₅+H]⁺ (m/z)

mp=292° C., dec.

EXAMPLE 278-Fluoro-3-methyl-6-oxo-9-[3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (57d)

Step A: Preparation of 55d

To a 0° C. solution of 14 (1.67 g, 8.96 mmol, 1.0 eq.) indichloromethane (25 mL), Et₃N (2.5 mL, 17.93 mmol, 2.0 eq.) was added.After 30 minutes, trifluoroacetic anhydride (1.9 mL, 13.45 mmol, 1.5eq.) was added slowly with 20 mg of DMAP and the reaction was stirred atroom temperature overnight. The mixture was diluted with dichloromethaneand washed with water; the organic extracts were dried over anhydroussodium sulfate. The resulting crude product was purified by flashchromatography on silica gel, eluting with cyclohexane-ethyl acetate(9:1 to 7:3) to afford 55d (2.03 g, 80%) as a clear oil.

Step B: Preparation of 56d

Utilizing the procedure described in the preparation of 4a-4b exceptsubstituting 3a-3b for 55d (2.03 g, 7.21 mmol, 1.0 eq.). The residue wasused without further purification; 56d (TFA salt) was obtained as alight yellow oil (2.44 g, quantitative).

MS (ESI⁺) (+0.1% HCOOH): 182.91 [C₆H₉F₃N₂O+H]⁺ (m/z)

Step C:8-Fluoro-3-methyl-6-oxo-9-[3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-hydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (57d)

Utilizing the procedure for the preparation of 5a, except substituting4a for 56d (1.2 g, 4.05 mmol, 3.0 eq.); the reaction mixture wasfiltered and the precipitate was triturated with boiling methanol andfiltrated to afford the title compound as a yellow solid (263 mg, 42%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 444.9 [C₁₈H₁₆F₄N₄O₅+H]⁺ (m/z)

mp=281-283° C.

EXAMPLE 288-Fluoro-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (57e)

Utilizing the procedure for the preparation of 5a, except substituting4a for 56e{Herling, 2003 #23}(1.0 g, 3.38 mmol, 3.0 eq.). The reactionmixture was filtered and the precipitate was triturated with boilingmethanol and filtrated to afford the title compound as a yellow solid(64 mg, 13%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 445.3 [C₁₈H₁₆F₄N₄O₅+H]⁺ (m/z)

mp=273-275° C.

EXAMPLE 298-Fluoro-3-methyl-6-oxo-9-[(R)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (57f)

Utilizing the procedure for the preparation of 5a, except substituting4a for 56f{Hudson, 2006 #8}1.5 g, 5.06 mmol, 3.0 eq.). The reactionmixture was filtered and the precipitate was triturated with boilingmethanol and filtrated to afford the title compound as a yellow solid(375 mg, 50%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 445.2 [C₁₈H₁₆F₄N₄O₅+H]⁺ (m/z)

mp=273-275° C.

EXAMPLE 308-Fluoro-3-methyl-6-oxo-9-(3-trifluoromethanesulfonylamino-pyrrolidin-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (60a)

Step A: Preparation of 58a

To a 0° C. solution of 14 (1.5 g, 8.05 mmol, 1.0 eq.) in dichloromethane(30 mL), Et₃N (3.4 mL, 24.16 mmol, 3.0 eq.) was added. After 15 minutes,trifluoromethanesulfonic anhydride (1.7 mL, 9.66 mmol, 1.2 eq.) wasadded slowly and the reaction was stirred at room temperature for 6hours. The mixture was diluted with dichloromethane and washed with asaturated aqueous NaHCO₃ solution; the organic extracts were dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresulting crude product was purified by flash chromatography on silicagel, eluting with cyclohexane-ethyl acetate (9:1 to 6:4) to afford 58a(1.1 g, 42%) as a pale yellow oil.

Step B: Preparation of 59a

Utilizing the procedure described in the preparation of 4a-4b exceptsubstituting 3a-3b for 58a (1.1 g, 3.45 mmol, 1.0 eq.). The residue waspurified by flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 15% methanol) 59a (TFAsalt) was obtained as a yellow oil (1.0 g, 87%).

Step C:8-Fluoro-3-methyl-6-oxo-9-(3-trifluoromethanesulfonylarnino-pyrrolidin-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (60a)

Utilizing the procedure for the preparation of 5a, except substituting4a for 59a (1.0 g, 3.01 mmol, 3.5 eq.), was evaporated under reducedpressure. The crude solid was triturated with methanol and filtratedthen the precipitate was triturated with boiling methanol and filtratedto afford the title compound as a yellow solid (30 mg, 6%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 459.0 [C₁₇H₁₆F₄N₄O₆S+H]⁺ (m/z)

mp=270-272° C.

EXAMPLE 318-Fluoro-9-(3-methanesulfonylamino-pyrrolidin-1-yl)-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (60b)

Utilizing the procedure described in the preparation of 5c exceptsubstituting 4c for 59b {Ueda, 1999 #24}(1.22 g, 7.44 mmol, 4.0 eq.).The reaction was evaporated under reduced pressure; the residue wastriturated with ethanol and filtrated. The solid was then trituratedwith a mixture of dichloromethane/methanol and filtrated to afford thetitle compound as a yellow solid (390 mg, 49%)

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 426.87 [C₁₇H₁₉FN₄O₆S+H]⁺ (m/z)

mp=261° C., dec.

EXAMPLE 328-fluoro-9-[(R,S)-4-hydroxy-3,3-dimethyl-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (75a)

Step A: Preparation of 73a

73a was prepared according to the procedure described by Di Cesare, etal, J. Med. Chem 1992, 35,(22) 4205-13, but starting with the(±)pantolactone.

Step B: Preparation of 74a

To a solution of 73a (1.0 g, 4.87 mmol, 1.0 eq.) in methanol (20 mL),Pd/C (100 mg) and SN HCl in isopropanol (1.95 ml, 9.74 mmol, 2.0 eq.)were added. The reaction mixture was submitted to hydrogenation atatmospheric pressure and room temperature for 48 hours. The mixture wasfiltrated over Celite® and evaporated under reduced pressure. Theresidue was purified by flash chromatography on silica gel, eluting withdichloromethane—7N NH₃ in methanol (gradient from 5% to 40% of 7N NH₃ inmethanol to afford the title compound as a white solid (170 mg, 30%).

Step C:8-fluoro-9-[(R,S)-4-hydroxy-3,3-dimethyl-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (75a)

Utilizing the procedure described in the preparation of 5c exceptsubstituting 4c for 74a (170 mg, 1.48 mmol, 2.0 eq.). The reaction wasevaporated under reduced pressure; the residue was triturated with waterand filtrated. The solid was then triturated with ethanol, filtrated andwashed with methanol. An analytical sample was obtained by preparativeTLC purification eluting with dichloromethane—2% methanol to afford thetitle compound as a yellow solid (40 mg, 14%).

HPLC (gradient 5% to 95% ACN in H₂O): >90%

MS (ESI⁺) (+0.1% HCOOH): 377.69 [C₁₈H₂₀FN₃O₅+H]⁺ (m/z)

mp=281° C., dec.

EXAMPLE 339-((R,S)-4-Amino-3,3-dimethyl-pyrrolidin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (75b)

Step A: Preparation of 74b

74b was prepared according to the procedure described by Di Cesare, etal, J. Med. Chem 1992, 35,(22) 4205-13, but starting with the(±)pantolactone.

Step B:9-((R,S)-4-Amino-3,3-dimethyl-pyrrolidin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (75b).

Utilizing the procedure described for the preparation of 5a, 75b wasobtained with TNOC (304 mg, 1.07 mmol, 1.0 eq.), 74b{Di Cesare, 1992#11} (370 mg, 3.24 mmol, 3.0 eq.) in pyridine and n-methylmorpholine(0.24mL, 2.16 mmol, 2.0 eq.). The mixture was evaporated; the residuewas purified on SCX cartridge eluting with methanol—triethylamine(gradient from 0% to 1% of triethylamine) to afford the title compoundas a yellow solid (40 mg, 21%)

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 376.93 [C₁₈H₂₁FN₄O₄+H]⁺ (m/z)

mp=237° C., dec.

EXAMPLE 349-((S)-4-Amino-3,3-dimethyl-pyrrolidin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (75c)

Utilizing the procedure described for the preparation of 5a, 75c wasobtained with TNOC (630 mg, 2.23 mmol, 1.0 eq.), 74c{Di Cesare, 1992#11} (1.1 g, 7.30 mmol, 3.3 eq.) in pyridine and n-methylmorpholine (1.0mL, 9.10 mmol, 4.0 eq.). The mixture was evaporated; the residue wastriturated several times with boiling methanol and ethanol and filtratedto afford the title compound as a yellow solid (144 mg, 10%)

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 377.4 [C₁₈H₂₁FN₄O₄+H]⁺ (m/z)

mp=230° C., dec.

EXAMPLE 359-((R)-4-Amino-3,3-dimethyl-pyrrolidin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (75d)

Utilizing the procedure described for the preparation of 5a, 75d wasobtained with TNOC (140 mg, 0.50 mmol, 1.0 eq.), 74d (200 mg, 1.33 mmol,2.7 eq.) in 5 mL of pyridine and n-methylmorpholine (0.20 mL, 0.91 mmol,3.6 eq.). The mixture was evaporated; the residue was triturated severaltimes with boiling methanol and filtrated to afford the title compoundas a yellow solid (60 mg, 31%)

HPLC (gradient 5% to 95% ACN in H₂O): >90%

MS (ESI⁺) (+0.1% HCOOH): 377.4 [C₁₈H₂₁FN₄O₄+H]⁺ (m/z)

mp=222° C., dec.

EXAMPLE 368-Fluoro-9-(3-hydroxy-3-thiazol-2-yl-pyrrolidin-1-yl)-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (82)

Step A: Preparation of 80

To a −70° C. solution of bromothiazole (0.8 mL, 8.77 mmol, 1.1 eq.) indiethyl ether, 2.5 N butyl lithium in hexanes (3.2 mL, 7.98 mmol, 1.0eq.) was added. After 15 minutes, a solution of3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1.47 g, 7.98 mmol,1.0 eq.) in tetrahydrofurane (20 mL) was added. The mixture was allowedto reach room temperature after 45 minutes. A saturated aqueous ammoniumchloride was added with 20 mL of ethyl acetate, the mixture was decantedand the organic phase was washed with water. The organic extracts weredried over sodium sulphate and evaporated under reduced pressure. Theresulting crude product was purified by flash chromatography on silicagel, eluting with cyclohexane-ethyl acetate (9:1 to 7:3) to afford 80(1.41 g, 66%) as a light yellow oil.

Step B: Preparation of 81

Utilizing the procedure described in the preparation of 4a-4b exceptsubstituting 3a-3b for 80 (1.41 g, 5.21 mmol). The residue was purifiedby flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 20% methanol). The titlecompound (trifluoroacetic acid salt) was obtained as a light brown oil(1.4mg, 74%).

Step C:8-Fluoro-9-(3-hydroxy-3-thiazol-2-yl-pyrrolidin-1-yl)-3-methyl-6-oxo-2,3-dihydro-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (82)

Utilizing the procedure described for the preparation of 5a, 82 wasobtained with TNOC (475 mg, 1.68 mmol, 1.0 eq.), 81 as a trifluoroaceticacid salt-(1.4 g, 5.05 mmol, 3.0 eq.) in 6 mL of pyridine andn-methyhnorpholine (1.5 mL). The reaction was evaporated under reducedpressure and the residue was triturated with boiling methanol andfiltrated to afford the title compound as a yellow solid (476 mg, 67%)

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 432.9 [C₁₉H₁₇FN₄O₅S+H]⁺ (m/z)

mp=252-253° C.

EXAMPLE 378-Fluoro-9-[3-(1-hydroxy-ethyl)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (88)

Step A: Preparation of 84

Compound 84 was prepared according to the preparation reported inW02005/026154 except substituting 1-(1R-phenyl-ethyl)-pyrrolidin-2-onefor the commercially available 1-benzyl-2-pyrrolidinone (7.0 g, 39.95mmol, 1.0 eq.). 84 was obtained as a brown oil (9.15 g, 84%).

Step B: Preparation of 85

Compound 85 was prepared according to the preparation reported inWO2005/026154 except substituting3-(2,2,2-trifluoro-acetyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one for 84(3.25 g, 11.9 mmol, 1.0 eq.) and zinc borohydride for potassiumborohydride. 85 was obtained as a pale yellow oil (2.95 g, 89%).

Step C: Preparation of 86

Compound 86 was prepared according to the preparation reported inWO2005/026154 except substituting3-(2,2,2-trifluoro-1-hydroxy-ethyl)-1-(lR-phenyl-ethyl)-pyrrolidin-2-onefor 84 (2.95 g, 10.79 mmol, 1.0 eq.), 86 was obtained as a pale yellowoil (2.68 g, 94%).

MS (ESI⁺) (+0.1% HCOOH): 260.17 [C₁₃H₁₆F₃NO+H]⁺ (m/z)

Step D: Preparation of 87

To a solution of 86 (1.7 g, 6.55 mmol, 1.0 eq.) in methanol (25 mL),Pd/C (200 mg) and SN HCl in isopropanol (3.0 mL, 15.0 mmol, 2.3 eq.)were added. The reaction mixture was submitted to hydrogenation at 8bars and at 40° C. for 24 hours. The mixture was filtrated over Celite®and evaporated under reduced pressure. The residue was purified by flashchromatography dichloromethane—methanol (gradient from 5% to 20% ofmethanol) to afford the title compound (208 mg, 15%) as a pale greenoil.

MS (ESI⁺) (+0.1% HCOOH): 170.1 [C₆H₁₀F₃N₀+H]⁺ (m/z)

Step E:8-Fluoro-9-[3-(1-hydroxy-ethyl)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (88)

Utilizing the procedure described for the preparation of 5a, 88 wasobtained from TNOC (300 mg, 1.06 mmol, 1.0 eq.) and 87 as ahydrochloride salt-(707 mg, 3.44 mmol, 3.2 eq.) in 10 mL of pyridine andtriethylamine (0.80 mL, 5.73 mmol, 5.4 eq.). The reaction was evaporatedunder reduced pressure and the residue was purified by preparative TLCpurification eluting with dichloromethane and 5% of methanol to affordthe title compound as a yellow solid (I9 mg, 7%)

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 432.3 [C₁₈H₁₇F₄N₃O₅+H]⁺ (m/z)

mp=308-310° C.

EXAMPLE 388-Fluoro-9-[3-(hydroxy-thiazol-2-yl-methyl)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (92)

Step A: Preparation of 89

Compound 89 was prepared according to the procedure reported inW02005/026154 except substitutingbenzyloxycarbonyl-pyrrolidin-3-yl-methanol for the commerciallyavailable 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester6 (3.4 g, 17.06 mmol, 1.0 eq.). 89 was obtained as a yellow oil (2.15 g,82%).

Step B: Preparation of 90

Compound 90 was prepared according to the procedure reported inW02005/026154 except substitutingbenzyloxycarbonyl-pyrrolidin-3-yl-thiazol-2-yl-methanol for 89 (2.15 g,10.79 mmol, 1.0 eq.). 89 was obtained as a yellow oil (2.39 g, 78%).

Step C: Preparation of 91

Utilizing the procedure described in the preparation of 4a-4b exceptsubstituting 3a-3b for 89 (1.65 g, 5.80 mmol). The residue was purifiedby flash chromatography on silica gel, eluting withdichloromethane—20%methanol then dichloromethane—20% 7N NH₃ in methanol,the title compound was obtained as a colorless oil (1.3 g,quantitative).

MS (ESI⁺) (+0.1% HCOOH): 185.02 [C₈H₁₂N₂OS+H]⁺ (m/z)

Step D:8-Fluoro-9-[3-(hydroxy-thiazol-2-yl-methyl)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (92)

Utilizing the procedure for the preparation of 10b except substituting9b for 91 (1.3 g, 7.05 mmol, 3.6 eq.). The reaction was evaporated underreduced pressure; the residue was triturated with boiling methanol andfiltrated to afford the title compound as a yellow solid (610 mg, 70%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 446.9 [C₂₀H₁₉FN₄O₅S+H]⁺ (m/z)

mp=215-217° C.

EXAMPLE 399-[3-(Amino-thiazol-2-yl-methyl)-pyrrolidin-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (96)

Step A: Preparation of 93

To a 0° C. solution of 90 (2.35 g, 8.26 mmol, 1.0 eq.) indichloromethane (60 mL), triethylamine (2.3 mL, 16.50 mmol, 2.0 eq.) andmethanesulfonyl chloride (1.3 mL, 16.80 mmol, 2.0 eq.) were added. Thereaction mixture was stirred at room temperature for 6 hours and washedfirst with aqueous 1 N HCl and then with a saturated aqueous NaHCO₃solution. The organic extracts were dried over sodium sulphate andevaporated under reduced pressure. The crude residue was dissolved indimethylformamide and sodium azide (2.7 g, 41.53 mmol, 5.0 eq.) wereadded, the reaction was heated at 85° C. for 16 hours. A saturatedaqueous ammonium chloride solution was added and the mixture wasextracted with ethyl acetate, the solution was then washed with watertwice, the organic extracts were dried over sodium sulphate andevaporated under reduced pressure. The resulting crude product waspurified by flash chromatography on silica gel, eluting withcyclohexane-ethyl acetate (7:3) to afford 93 (2.1 g, 82%) as a yellowoil.

Step B: Preparation of 94

Compound 94 was prepared according to the procedure described inEP1182202 except substituting4-(R)-[1-azido-1-(thiazol-2-yl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidinonefor 93 (1.5 g, 4.84 mmol, 1.0 eq.). 94 was obtained as a colorless oil(1.3 g, 70%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 384.3 [C₁₈H₂₉N₃O₄S+H]⁺ (m/z)

Step C: Preparation of 95

Compound 95 was prepared according to the procedure described inE1182202 except substituting 3-(R)-[1-tert-butoxycarbonylamino-1-(thiazol-2-yl)methyl]-1 benzyloxycarbonyl pyrrolidinefor 94 (1.3 g, 3.39 mmol, 1.0 eq.). 95 (di-trifluoroacetic acid salt)was obtained as a colorless oil (1.35 g, quantitative).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 184.1 [C₈H₁₃N₃S+H]⁺ (m/z)

Step D:9-[3-(Amino-thiazol-2-yl-methyl)-pyrrolidin-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (96)

Utilizing the procedure described for the preparation of 5a, 96 wasobtained from TNOC (80 mg, 0.28 mmol, 1.0 eq.) and 90 (200 mg, 0.49mmol, 1.7 eq.) in 5 mL of pyridine and triethylamine (1.3 mL). Thereaction was evaporated under reduced pressure and the residue waspurified by preparative TLC purification eluting with dichloromethaneand 5% of methanol to afford the title compound as a yellow solid (34mg, 27%)

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 446.1 [C₂₀H₂₀FN₄O₅S+H]⁺ (m/z)

mp=233-235° C.

EXAMPLE 408-fluoro-9-{3-[(Z/E)-methoxyimino]-pyrrolidin-1-yl}-3-methyl-6-oxo-2,3-dihydro-6-H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (105)

Step A: Preparation of 103

To a −78° C. solution of oxalyl chloride (0.5 mL, 5.73, mmol, 2.2 eq.)in dichloromethane (30 mL) were added dimethylsulfoxide (0.75 mL, 10.58mmol, 4.0 eq.) and a solution of9-{3-hydroxy-pyrrolidin-1-yl}-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6-H-1-oxa-3,3a-diaza-phenalene-carboxylicacid benzyl ester 102 (1.16 g, 2.64 mmol, 1.0 eq.) in dichloromethane(30 mL). After 1 hour at -78° C., triethylamine (2.2 mL, 15.78 mmol, 6.0eq.) was added. The reaction mixture was stirred 1 hour at −78° C., andthen 1 hour at room temperature. The mixture was diluted withdichloromethane and washed with water; the organic extracts were driedover sodium sulphate and evaporated under reduced pressure. 103 wasobtained as a beige solid (1.15g, quantitative).

MS (ESI⁺) (+0.1% HCOOH): 438.3 [C₂₃H₂₀FN₃O₅+H]⁺ (m/z)

Step B: Preparation of 104

To a suspension 103 (1.15 g, 2.63 mmol, 1.0 eq.) in ethanol (25 mL) andTHF (15 mL) were added methoxylamine hydrochloride (820 mg, 9.82 mmo,3.7 eq) and a solution of sodium bicarbonate (750 mg, 8,93 mmol, 3.4 eq)in water (8 mL). The mixture was strirred at 40° C. for 16 hours. Thereaction was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate and washed first with water and then withbrine. The organic extracts were dried over anhydrous sodium-sulphateand were evaporated under reduced pressure to afford the title compoundas a beige solid (1.19 g, 97%).

HPLC (gradient 5% to 95% ACN in H₂O): >90%

MS (ESI⁺) (+0.1% HCOOH): 467.4 [C₂₄H₂₃FN₄O₅+H]⁺ (m/z)

Step C:8-fluoro-9-{3-[(Z/E)-methoxyimino]-pyrrolidin-1-yl}-3-methyl-6-oxo-2,3-dihydro-6-H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (105)

A suspension of 104 (1.19 g, 2.55 mmol, 1.0 eq) in dichloromethane (25mL) and methanol (10 mL) was added palladium on activated carbon 10%(300 mg, 0.25 mmol, 0.1 eq). The mixture was submitted to hydrogenationat room temperature under 1 atmosphere for 3 hours. The reaction mixturewas filtered through Celite and evaporated. The residue was trituratedwith methanol and the solid was filtered to afford the title compound asa yellow solid (800 mg, 83%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 377.2 [C₁₆H₁₇FN₄O₅+H]⁺ (m/z)

mp=241-243° C.

EXAMPLE 418-Fluoro-3-methyl-6-oxo-9-[4-(pyrazin-2-ylamino)-piperidin)-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (108a)

Step A: Preparation of 106a

In a sealed tube, 30 mL of dry toluene was degazed with Argon during 15minutes, palladium acetate (114 mg, 0.17 mmol, 0.04 eq.) andracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (106 mg, 0.17 mmol,0.04 eq.) were added and the mixture was degazed with Argon for 10minutes. Then 2-chloropyrazine (500 mg, 4.37 mmol, 1.0 eq.),4-amino-1-Boc-piperidine (1.05 g, 5.24 mmol, 1.2 eq.) and sodiumtert-butoxide (587 mg, 6.11 mmol, 1.4 eq.) were added and the mixturewas stirred at 70° C. overnight. The reaction was concentrated invacuum. The resulting crude product was purified by flash chromatographyon silica gel, eluting with 100% ethyl acetate to afford 106a (1.0 g,82%).

Step B: Preparation of 107a

According to general procedure B except substituting TFA for 4N HCl indioxane, 28a (1.4 g, 5.03 mmol, 1.0 eq.) was deprotected; the residuewas purified by flash chromatography on silica gel, eluting with elutingdichloromethane 7N NH₃ in methanol (gradient from 5% to 20% of 7N NH₃ inmethanol) to afford 107a (900 mg, quantitative).

MS (ESI⁺) (+0.1% HCOOH): 179.24 [C₉H₁₄N₄+H]⁺ (m/z)

Step C:8-Fluoro-3-methyl-6-oxo-9-[4-(pyrazin-2-ylamino)-piperidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (108a)

According to general procedure A, TNOC (355 mg, 1.26 mmol, 1.0 eq.) wascoupled with 29a (900 mg, 5.05 mmol, 4.0 eq.) and N-methylmorpholine(0.28 mL, 2.53 mmol, 2.0 eq.). The residue was triturated several timeswith hot methanol to afford the title compound as a beige solid (67 mg,12%).

HPLC (gradient 5%-80% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 441.14 [C₂₁H₂₁FN₆O₄+H]⁺ (m/z)

mp=239° C., dec.

EXAMPLE 428-Fluoro-3-methyl-6-oxo-9-[4-(pyridin-2-ylamino)-piperidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (108b)

Step A: Preparation of 106b

Utilizing the procedure described for the preparation of 107a exceptsubstituting 2-chloropyrazine for 2-chloropyridine (4.4 mmol). Theresulting crude product was purified by flash chromatography on silicagel, eluting with cyclohexane-ethyl acetate (1:1) to afford 106b (1.2 g,98%).

Step B: Preparation of 107b

According to general procedure B, 106b (1.2 g, 4.31 mmol, 1.0 eq.) wasdeprotected; the residue was purified by flash chromatography on silicagel, eluting with eluting dichloromethane 7N NH₃ in methanol (gradientfrom 0% to 20% of 7N NH₃ in methanol) to afford 107b (1.0 g,quantitative).

MS (ESI⁺) (+0.1% HCOOH): 178.18 [C₁₀H₁₅N₃+H]⁺ (m/z)

Step C:8-Fluoro-3-methyl-6-oxo-9-[4-(pyridin-2-ylamino)-piperidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (108b)

According to general procedure A, TNOC (530 mg, 1.88 mmol, 1.0 eq.) wascoupled with 107b (1.0 g, 5.54 mmol, 3.0 eq.) and N-methylmorpholine(0.41 mL, 3.76 mmol, 2.0 eq.). The residue was triturated several timeswith hot methanol, an analytical sample was obtained by preparative TLCpurification eluting with dichloromethane—methanol (gradient from 2.5%to 5% of methanol) to afford the title compound as a yellow solid (80mg, 10%).

HPLC (gradient 5%-80% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 440.1 [C₂₂H₂₂FN₅O₄+H]⁺ (m/z)

mp=264° C., dec.

EXAMPLE 438-fluoro-3-methyl-6-oxo-9-[4-(thiazol-2-ylamino)-piperidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (111)

Step A: Preparation of 109

To a 0° C. solution of the commercially available tert-butyl4-hydroxy-1-piperidine-carboxylate (1.5 g, 7.45 mmol, 1.2 eq.) in dryTHF (20 mL), triphenylphosphine (2.4 g, 9.31 mmol, 1.5 eq.) was added.After complete dissolution, diethylazodicarboxylate—40% w/v in toluene-(4 mL, 9.31 mmol, 1.5 eq.) was added dropwise followed bythiazol-2-yl-carbamic acid tert-butyl ester g, 5.99 mmol, 1.0 eq.). Themixture was stirred at RT for 18 hours. The reaction was evaporatedunder reduced pressure. The resulting crude product was purified byflash chromatography on silica gel, eluting with cyclohexane-ethylacetate (95:5 to 85:15) to afford 109 as a colorless gum (1.95 g, 85%)

Step B: Preparation of 110

109 (1.95 g, 5.08 mmol) was dissolved in ethyl acetate (10 mL) and 4NHCl in dioxane (10 mL) was added. The mixture was stirred at roomtemperature for 6 hours and one hour at 60° C. with few drops of TFA.The reaction was concentrated in vacuum. The residue was purified byflash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 5% to 10% methanol) thendichloromethane—7N NH₃ in methanol (gradient from 20% to 50% of 7N NH₃in methanol). The title compound was obtained as a white solid (875 mg,93%).

MS (ESI⁺) (+0.1% HCOOH): 184.18 [C₈H₁₃N₃S+H]⁺ (m/z)

Step C:8-fluoro-3-methyl-6-oxo-9-[4-(thiazol-2-ylamino)-piperidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (111)

According to general procedure A, TNOC (336 mg, 1.19 mmol, 1.0 eq.) wascoupled with 34 (875 mg, 4.77 mmol, 4.0 eq.) and 1 mL ofN-methylmorpholine. The residue was triturated with water and filtered(227 mg crude), an analytical sample was obtained by preparative TLCpurification eluting with dichloromethane—methanol (gradient from 2.5%to 5% of methanol) to afford the title compound as a beige solid (36 mg,7%).

HPLC (gradient 5%-80% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 445.9 [C₂₀H₂₀FN₅O₄S+H]⁺ (m/z)

mp=280° C.

EXAMPLE 448-Fluoro-9-{4-[furan-2-carbonyl)-amino]-piperidin-1-yl}-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (114)

Step A: Preparation of 112

According to general procedure C, 112 was obtained with4-amino-1-Boc-piperidine (3.7 g, 18.60 mmol, 1.0 eq.), EDCI(5.1 g, 27.88mmol, 1.5 eq.), HOBt (3.61 g, 27.88 mmol, 1.5 eq.) andfuran-2-carboxylic acid (2.5 g, 22.30 mmol, 1.2 eq.). The mixture waswashed with a saturated solution of sodium bicarbonate; the residue waspurified by flash chromatography on silica gel, eluting with elutingwith cyclohexane-ethyl acetate (8:2 to 0:1) to afford 112 as a colorlessoil (5.1 g, 97%).

Step B: Preparation of 113

According to general procedure B, 112 (5.1 g, 17.32 mmol, 1.0 eq.) wasdeprotected; the residue was purified by flash chromatography on silicagel, eluting with eluting with dichloromethane—10% methanol thendichloromethane—7N NH₃ in methanol (gradient from 10% to 30% of 7N NH₃in methanol) to afford 113 as a white foam (3.0 g, 89%).

Step C:8-Fluoro-9-{4-[(furan-2-carbonyl)-amino]-piperidin-1-yl}-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (114)

According to general procedure A, TNOC (340 mg, 1.20 mmol, 1.0 eq.) wascoupled with 37 (700 mg, 3.60 mmol, 3.0 eq.) and 1 mL ofN-methylmorpholine. The residue was triturated with methanol andfiltered to afford the title compound as a beige solid (175 mg, 32%).

HPLC (gradient 5%-80% ACN in H₂O): >90%

MS (ESI⁺) (+0.1% HCOOH): 457.0 [C₂₂H₂₁FN₅O₆+H]⁺ (m/z)

mp=293-295° C.

EXAMPLE 459-[1,4′]Bipiperidinyl-1′-yl-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (54g)

According to general procedure A, TNOC (391 mg, 1.39 mmol, 1.0 eq.) wascoupled with N-(4-Piperidino)piperidine (commercially available) (700mg, 4.16 mmol, 3.0 eq.) in 5 mL of pyridine and N-methylmorpholine(0.305 mL, 2.77 mmol, 2.0 eq.) The reaction was evaporated under reducedpressure, the residue was purified by preparative TLC purificationeluting with dichloromethane—methanol (gradient from 2.5% to 10% ofmethanol) to afford the title compound as a yellow solid (65 mg, 11 %)

HPLC (gradient 5% to 80% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 431.27 [C₂₂H₂₇FN₄O₄+H]⁺ (m/z)

mp=249° C., dec.

EXAMPLE 468-Fluoro-3-methyl-6-oxo-9-(4-pyrrolidin-1-yl-piperidin-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (116)

According to general procedure A, TNOC (300 mg, 1.06 mmol, 1.0 eq.) wascoupled with 4-(1-pyrrolidinyl)piperidine (commercially available) (500mg, 3.24 mmol, 3.0 eq.) in 5 mL of pyridine and 1 mL ofN-methyhnorpholine. The reaction was evaporated under reduced pressure;the residue was triturated with boiling methanol to afford the titlecompound as a yellow solid (240 mg, 54%)

HPLC (gradient 5% to 80% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 417.0 [C₂₁H₂₅FN₄O₄+H]⁺ (m/z)

mp=267-269° C.

EXAMPLE 473-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (117)

Utilizing the procedure described for the preparation of 5a, 117 wasobtained from the corresponding 8-des-fluoro-9-fluoro compound (preparedaccording to the procedure described in U.S. Pat. No. 4,801,584) (100mg, 0.38 mmol, 1.0 eq.) and 56e (340 mg, 1.15 mmol, 3.0 eq.) in 2.5 mLof dry pyridine and N-methylmorpholine (0.2 mL, 1.82 mmol, 4.8 eq.). Thereaction was evaporated under reduced pressure. The residue wastriturated with boiling methanol to afford the title compound as ayellow solid (25 mg, 15%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 427.05 [C₁₈H₁₇F₃N₄O₅+H]⁺ (m/z)

mp=310° C. dec.

EXAMPLE 483-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (118)

Utilizing the procedure described for the preparation of 5a, 118 wasobtained from the 8-des-fluoro-9-fluoro compound (prepared according tothe procedure described in US4801584) (100 mg, 0.38 mmol, 1.0 eq.) and35b (480 mg, 1.21 mmol, 3.2 eq.) in 2.5 ml of dry pyridine andN-methylmorpholine (0.2 mL, 1.82 mmol, 4.8 eq.). The reaction wasevaporated under reduced pressure. The residue was triturated withboiling methanol and purified by preparative T.L.C. to afford the titlecompound as a yellow solid (20 mg, 13%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 414.0 [C₁₉H₁₉N₅O₄S+H]⁺ (m/z)

mp=275° C. dec.

EXAMPLE 499-((R)-4-amino-3,3-dimethyl-pyrrolidin-1-yl)-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

By using the preparation method of 5a, product X is obtained startingwith the corresponding 8-des-fluoro-9-fluoro product (prepared accordingto the method described in US-4,801-584) (80 mg, 0.30 mmol, 1.0 eq.) andfrom product 56e (200 mg, 1.33 mmol, 4.4 eq.) in 3 mL of anhydrouspyridine and 0.30 mL of N-methylmorpholine (2.73 mmol, 9.0 eq.). Thereaction mixture is evaporated under reduced pressure and the residue istriturated in methanol, and then purified by preparative TLC. Theexpected product is obtained as a yellow solid (11 mg, 12%).

EXAMPLE 508-fluoro-2-methyl-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (121)

Step A: Preparation of 119

A suspension of TNOC (10.0 g, 35.43 mmol, 1.0 eq) in an aqueous solutionof 5N NaOH (200 mL) was stirred at 95° C. for 6 hours. The mixture wascooled to room temperature and an aqueous solution of 6N HCl was addeduntil precipitation. The precipitate was filtered, washed with water anddiethylether and dried to afford the title compound as a white solid(9.1 g, 95%).

MS (ESI⁺) (+0.1% HCOOH): 271.0 [C₁₁H₈F₂N₂O₄+H]⁺ (m/z)

Step B: Preparation of 120

In a sealed tube, 119 (1.5 g, 5.55 mmol, 1.0 eq.) and acetaldehyde (40mL, 713 mmol) were suspended in 100 mL of dry dioxane. The reactionmixture was stirred at 110° C. for 18 hours. The reaction was cooled toroom temperature, the precipitate formed was filtered, washed withmethanol and diethylether, and dried to afford the title compound as awhite solid (1.1 g, 69%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 297.0 [C₁₃H₁₀F₂N₂O₄+H]⁺ (m/z)

Step C:8-fluoro-2-methyl-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (121)

Utilizing the procedure described for the preparation of 5a, 121 wasobtained from 120 (100 mg, 0.34 mmol, 1.0 eq.) and 56e (300 mg, 1.01mmol, 3.0 eq.) in 2 mL of dry pyridine and N-methylmorpholine (0.2 mL,1.82 mmol, 5.0 eq.). The reaction was evaporated under reduced pressure.The residue was recristallized in methanol to afford the title compoundas a yellow solid (54 mg, 35%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 459.3 [C₁₉H₁₈ F₄N₄O₅+H]⁺ (m/z)

mp=242° C.-245° C.

EXAMPLE 51 8-fluoro-2, 2-methyl-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (123)

Step A: Preparation of 122

Utilizing the procedure described for the preparation of 120, 122 wasobtained from 119 (500 mg, 1.85 mmol, 1.0 eq.) and dry acetone (6.2 mL,89 mmol) in 20 mL of dry dioxane. The reaction was evaporated underreduced pressure. The residue was triturated with boiling methanol toafford the title compound as a white solid (610 mg, 100%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 311.1 [C₁₄H₁₂ F₂N₂O₄+H]⁺ (m/z)

Step B:8-fluoro-2,2-methyl-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (123)

Utilizing the procedure described for the preparation of 5a, 123 wasobtained from 122 (100 mg, 0.32 mmol, 1.0 eq.) and 56e (280 mg, 0.96mmol, 3.0 eq.) in 2 mL of dry pyridine and N-methylmorpholi (0.2 mL,1.82 mmol, 5.0 eq.). The reaction was evaporated under reduced pressure.The residue was purified by preparative T.L.C. and triturated indiethylether to afford the title compound as a yellow solid (35 mg,23%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 473.2 [C₂₀H₂₀ F₄N₄O₅+H]⁺ (m/z)

mp=217° C.-219° C.

EXAMPLE 522-methyl-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (126)

Step A: Preparation of 124

Compound 124 was prepared according to the procedure described in U.S.Pat. No. 4,801,584.

Step B: Preparation of 125

Utilizing the procedure described for the preparation of 120, 125 wasobtained from 124 (400 mg, 1.43 mmol, 1.0 eq.) and acetaldehyde (12.0mL, 214 mmol) in 30 mL of dry dioxane. The reaction was evaporated underreduced pressure. The residue was triturated with boiling methanol toafford the title compound as a brown solid (305 mg, 77%).

HPLC (gradient 5% to 95% ACN in H₂O): >90%

MS (ESI⁺) (+0.1% HCOOH): 279.0 [C₁₃H₁₁FN₂O₄+H]⁺ (m/z)

Step C:2-methyl-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (126)

Utilizing the procedure described for the preparation of 5a, 126 wasobtained from 125 (100 mg, 0.36 mmol, 1.0 eq.) and 56e (210 mg, 1.05mmol, 2.9 eq.) in 2 mL of dry pyridine and N-methylmorpholine (0.2 mL,1.82 mmol, 5.0 eq.). The reaction was evaporated under reduced pressure.The residue was triturated in diethylether and purified by T.L.C.preparative to afford the title compound as a yellow solid (21 mg, 13%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 441.2 [C₁₉H₁₉F₃N₄O₅+H]⁺ (m/z)

Mp=260° C.

EXAMPLE 532,2-methyl-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (128)

Step A: Preparation of 127

Utilizing the procedure described for the preparation of 120, 127 wasobtained from 124 (400 mg, 1.43 mmol, 1.0 eq.) and dry acetone (4.0 mL,57.3 mmol) in 13 mL of dry dioxane. The reaction was evaporated underreduced pressure. The residue was triturated with boiling methanol toafford the title compound as a brown solid (338 mg, 70%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 293.1 [C₁₄H₁₃ FN₂O₄+H]⁺ (m/z)

Step B:2,2-methyl-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (128)

Utilizing the procedure described for the preparation of 5a, 128 wasobtained from 127 (110 mg, 0.38 mmol, 1.0 eq.) and 56e (340 mg, 1.15mmol, 3.0 eq.) in 2 mL of dry pyridine and N-methylmorpholine (0.2 mL,1.82 mmol, 5.0 eq.). The reaction was evaporated under reduced pressure.The residue was triturated in methanol and purified by preparativeT.L.C. to afford the title compound as a yellow solid (20 mg, 12%).

HPLC (gradient 5% to 95% ACN in H₂O): >95%

MS (ESI⁺) (+0.1% HCOOH): 455.1 [C₂₀H₂₁F₃N₄O₅+H]⁺ (m/z)

mp=283° C.

EXAMPLE 548-fluoro-2-methyl-3-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (129)

Utilizing the procedure described for the preparation of 5a, 129 wasobtained from 120 (300 mg, mmol, 1.0 eq.) and 35b (620 mg, 3.03 mmol,3.0 eq.) in 6 mL of dry pyridine and N-methylmorpholine (0.6 mL, 5.05mmol, 5.0 eq.). The reaction was evaporated under reduced pressure. Theresidue was purified by flash chromatography on silica gel, eluting withdichloromethane—methanol (gradient from 0% to 5% methanol) to afford thetitle compound as a yellow solid (50 mg, 15%).

HPLC (gradient 5% to 95% ACN in H₂O): >99%

MS (ESI⁺) (+0.1% HCOOH): 446.0 [C₂₀H₂₀FN₅O₄+H]⁺ (m/z)

mp=224° C.-226° C.

EXAMPLE 558-fluoro-2,2,3-trimethyl-6-oxo-9-[(R)-3-(thiazol-2ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (130)

By using the method for preparing 5a, the product 130 is obtainedstarting with 200 mg of product 112 (0.64 mmol, 1.0 eq.) and product 35b(770 mg, 1.93 mmol, 3.0 eq.) in 4 mL of anhydrous pyridine and 0.35 mLof N-methylmorpholine (3.20 mmol, 5.0 eq.). The reaction medium isevaporated under reduced pressure and the residue is purified bychromatography on silica and then by preparative TLC. The expectedproduct is obtained as a yellow solid (8 mg, 3%).

HPLC (5%-95% ACN gradient in H₂O); >90%

MS (ESI⁺) (+0.1%, HCOOH): 460.10 [C₂₁H₂₂FN₅O₄S+H]⁺ (m/z)

MP=235-237° C.

EXAMPLE 562,3-dimethyl-6-oxo-R-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-]-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (131)

By using the method for preparing 5a, the product 131 is obtainedstarting with 190 mg of product 125 (0.36 mmol, 1.0 eq.) and withproduct 35b (860 mg, 2.16 mmole, 3.2 eq.) in 5 mL of anhydrous pyridineand 0.5 mL of N-methylmorpholine (4.55 mmol, 6.7 eq.). The reactionmixture is evaporated under reduced pressure and the residue istriturated in ethyl ether and then purified by chromatography on silicaby eluting with a dichloromethane-methanol mixture (100:0 to 96:4) andthe expected product is obtained as a yellow solid (20 mg, 7%).

HPLC (5%-95% ACN gradient in H₂O); >99%

MS (ESI⁺) (+0.1%, HCOOH): 428.0 [C₂₀H₂₁N₅O₄S+H]⁺ (m/z)

MP=260-263° C.

EXAMPLE 572,2,3-trimethyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (132)

By using the method for preparing 5a, the product 132 is obtainedstarting with 200 mg of product 127 (0.68 mmol, 1.0 eq.) and of product35b (870 mg, 2.19 mmol, 3.2 eq.) in 5 mL of anhydrous pyridine and 0.5mL of N-methylmorpholine (4.55 mmol, 6.7 eq.). The reaction medium isevaporated under reduced pressure and the residue is triturated inmethanol and then purified by preparative TLC. The expected product isobtained as a yellow solid (21 mg, 7%).

HPLC (5%-95% ACN gradient in H₂O); >99%

MS (ESI⁺) (+0.1%, HCOOH): 442.0 [C₂₁H₂₃N₅O₄S+H]⁺ (m/z)

MP=287° C. (decomposition).

EXAMPLE 582,2,3-dimethyl-6-oxo-R-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (134)

Stage A: Preparation of 133

By using the method for preparing 120, the product 133 is obtainedstarting with 2.0 g of product 119 (7.40 mmol, 1.0 eq.), with 6.6 mL ofethyl diethoxy acetate (89 mmol) and 0.5 mL of trifluoroacetic acid(6.70 mmol, 0.9 eq.) in 80 mL of anhydrous dioxane. The expected productis obtained as a white solid (2.0 g, 76%).

HPLC (5%-95% ACN gradient in H₂O); >85%

MS (ESI⁺) (+0.1%, HCOOH): 355.1 [C₁₅H₁₂F₂N₂O₆+H]⁺ (m/z)

Stage B:2,2,3-trimethyl-6-oxo-9-[(R)-3-(thiazol-2-yl-amino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

By using the method for preparing 5a, the product 134 is obtainedstarting with 300 mg of product 133 (0.84 mmol, 1.0 eq.) and withproduct 35b (720 mg, 2.42 mmol, 3.0 eq.) in 6 mL of anhydrous pyridineand 0.45 mL of N-methylmorpholine (4.20 mmol, 5.0 eq.). The reactionmedium is evaporated under reduced pressure and the residue istriturated in methanol and then purified by preparative TLC. Theexpected product is obtained as a white solid (13 mg, 3%).

HPLC (5%-95% ACN gradient in H₂O); >95%

MS (ESI⁺) (+0.1%, HCOOH): 504.05 [C₂₂H₂₂FN₅O₆S+H]⁺ (m/z)

MP=287° C.

EXAMPLE 599-[(R)-4-amino-3,3-dimethyl-pyrrolidin-1-yl]-8-fluoro-2,3-dimethyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (135)

By using the method for preparing 5a, the product 135 is obtainedstarting with the product 120 (230 mg, 0.78 mmol, 1.0 eq.) and ofproduct 74b (200 mg, 1.33 mmol, 1.7 eq.) in 1 mL of anhydrous pyridineand 2 mL of anhydrous acetonitrile in the presence of DABCO (250 mg,2.23 mmol, 2.9 eq.). The reaction medium is filtered and the precipitateis washed with acetonitrile. The obtained solid is triturated inmethanol and washed with methanol and then with ethyl ether. Theexpected product is obtained as a yellow solid (105 mg, 34%).

HPLC (5%-95% ACN gradient in H₂O); >90%

MS (ESI⁺) (+0.1%, HCOOH): 391.0 [C₁₉H₂₃FN₄O₄+H]⁺ (m/z)

MP=212-214° C.

EXAMPLE 609-((R)-4-amino-3,3-dimethyl-pyrrolidin-1-yl)-8-fluoro-2,2,3-trimethyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (136)

By using the method for preparing 5a, the product 136 is obtainedstarting with the 220 mg of product 112 (0.71 mmol, 1.0 eq.) and ofproduct 74b (200 mg, 1.33 mmol, 1.9 eq.) in 4 mL of anhydrous pyridineand 2 mL of anhydrous acetonitrile in the presence of DABCO (250 mg,2.23 mmol, 3.1 eq.). The reaction medium is filtered and the precipitateis washed with acetonitrile. The obtained solid is triturated inmethanol and washed with methanol and then with ethyl ether. Theexpected product is obtained as a yellow solid (110 mg, 38%).

HPLC (5%-95% ACN gradient in H₂O); >90%

MS (ESI⁺) (+0.1%, HCOOH): 405.0 [C₂₀H₂₅FN₄O₄+H]⁺ (m/z)

MP=255-257° C.

EXAMPLE 619-[(S)-3,3-dimethyl-4-(thiazol-2-ylamino)-pyrrolidin-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (141)

Stage A: Preparation of 137

137 was prepared according to the method described by Di Cesare et al.,J. Med. Chem. 1992, 35, (22), 4205-13, by using (S)-pentolactone asstarting material.

Stage B: Preparation of 138

The compound 138 is obtained by following the method described in thepreparation of product 8a by substituting the product 137 for theproduct 6. The obtained raw product is purified by chromatography onsilica by eluting with a dichloromethane-methanol mixture (10:0 to 9:1)and the product 138 is obtained as a brown foam (385 mg, 25%).

Stage C: Preparation of 139

The product 138 (380 mg, 0.98 mmol, 1.0 eq.) is dissolved in 5 mL ofanhydrous chloroform and 0.28 mL of benzylchloroformate (1.99 mmol, 2.0eq.) are added. The mixture is stirred at 60° C. for 8 hours. Thereaction medium is diluted with dichloromethane and washed with asaturated sodium hydrogencarbonate solution. The isolated organicextracts are dried and the solvent is evaporated under reduced pressure.The raw expected product is obtained, which is purified bychromatography on silica by diluting with a cyclohexane-ethyl acetatemixture (10:0 to 9:1) and the expected product 139 is obtained as paleyellow oil (307 mg, 70%).

Stage D: Preparation of 140

The product 139 (300 mg, 0.70 mmol, 1.0 eq.) and sodium iodide (420 mg,2.80 mmol, 4.0 eq.) are dissolved in 5 mL of anhydrous acetonitrile.0.35 mL of chlorotrimethyl silane (2.77 mmol, 4.0 eq.) are then addeddropwise. The mixture is stirred at room temperature for 4 hours. Thereaction medium is diluted with 5 mL of methanol and then the solvent isevaporated under reduced pressure. The raw expected product is obtained,which is purified by chromatography on silica by eluting with adichloromethane-methanol mixture (10:0 to 9:1) subsequently with a SCXcolumn and the expected product 140 is obtained as a brown oil (85 mg,61%). Stage E:9-[(S)-3,3-dimethyl-4-(thiazol-2-ylamino)-pyrrolidin-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

By using the method for preparing 5a, the product 141 is obtainedstarting with 65 mg of “UBE-4” (0.23 mmol, 1.0 eq.) and with the product140 (80 mg, 0.41 mmol, 2.0 eq.) in 0.5 mL of anhydrous pyridine and 1 mLof acetonitrile in the presence of DABCO (50 mg, 0.45 mmol, 2.0 eq.).The reaction medium is filtered and the precipitate washed withacetonitrile. The obtained solid is triturated in methanol and washedwith methanol and then with ethyl ether. The expected product isobtained as a yellow solid (23 mg, 22%).

HPLC (5%-95% ACN gradient in H₂O); >95%

MS (ESI⁺) (+0.1%, HCOOH): 460.5 [C₂₁H₂₂FN₅O₄S+H]⁺ (m/z)

MP=265° C. (decomposition).

EXAMPLE 629-[(R)-3,3-dimethyl-4-(thiazol-2-ylamino)-pyrrolidin-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (146)

Stage A: Preparation of 142

142 was prepared according to the method described by Di Cesare et al.,J. Med. Chem. 1992, 35, (22), 4205-13, by using (R)-pantolactone asstarting material.

Stage B: Preparation of 143

Compound 143 is obtained by following the method described in thepreparation of 8a by substituting product 142 for product 6. Theobtained raw product is purified by chromatography on silica by elutingwith a dichloromethane-methanol mixture (10:0 to 93:7) and product 143is obtained as a yellow oil (865 mg, 22%).

Stage C: Preparation of 144

By using the method for preparing 139, product 144 is obtained with thestarting product 143 (860 mg, 1.13 mmol, 1.0 eq.). The expected rawproduct is obtained, which is purified by chromatography on silica byeluting with a cyclohexane-ethyl acetate mixture (10:0 to 9:1) and theexpected product is obtained as a colorless oil (445 mg, 91%).

Stage D: Preparation of 145

By using the method for preparing 140, product 145 is obtained with thestarting product 144 (420 mg, 0.97 mmol, 1.0 eq.). The raw expectedproduct is obtained, which is purified by chromatography on silica byeluting with a dichloromethane-methanol mixture (10:0 to 9:1),subsequently with a SCX column and the product 140 is obtained ascolorless oil (165 mg, 86%).

Stage E:9-[(R)-3,3-dimethyl-4-(thiazol-2-ylamino)-pyrrolidin-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

By using the method for preparing 5a, product 146 is obtained startingwith 115 mg of “UBE-4” (0.41 mmol, 1.0 eq.) and with product 145 (160mg, 0.81 mmol, 2.0 eq.) in 1 mL of anhydrous pyridine and 2 mL ofacetonitrile in the presence of DABCO (90 mg, 0.80 mmol, 2.0 eq.). Thereaction medium is filtered and the precipitate washed withacetonitrile. The obtained solid is triturated in methanol and washedwith methanol and then with ethyl ether. The expected product isobtained as a yellow solid (67 mg, 36%).

HPLC (5%-95% ACN gradient in H₂O); >95%

MS (ESI⁺) (+0.1%, HCOOH): 460.53 [C₂₁H₂₂FN₅O₄S+H]⁺ (m/z)

MP=271-273° C.

EXAMPLE 638-fluoro-3-methyl-6-oxo-9-((R)-3-[1,2,3]triazol-1-yl-pyrrolidin-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (149)

Stage A: Preparation of 147

The product is prepared according to the method described in US2003/0225107 by substituting the 3-(S)-azido-pyrrolidin-1-yl carbamicacid tert-butyl ester for the5(R)-azidomethyl-3-[4-(1-cyanocyclopropan-1-yl)phenyl]oxazolidin-2-one(1.1 g, 5.20 mmol, 1.0 eq.). The raw product is purified bychromatography on silica by eluting with a dichloromethane-methanolmixture (100:0 to 97:3) and 142 is obtained as an orange oil (681 mg,55%).

Stage B: Preparation of 148

The method described for preparing 4c is used by substituting product147 (680 mg, 2.85 mmol, 1.0 eq.) for product 3c with 17 mL of HCl 4N indioxane. The obtained raw product is subsequently used without anysubsequent purification.

Stage C:8-fluoro-3-methyl-6-oxo-9-((R)-3-[1,2,3]triazol-1-yl-pyrrolidin-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

The method described in preparation 5c is used by substituting product148 (400 mg, 2.30 mmol, 4.0 eq.) for product 4c. The reaction medium isevaporated under reduced pressure. The result is triturated in methanoland then purified by preparative TLC. The expected product is obtainedas a yellow solid (20 mg, 22%).

HPLC (5%-95% ACN gradient in H₂O); >95%

MS (ESI⁺) (+0.1%, HCOOH): 401.4 [C₁₈H₁₇FN₆O₄+H]⁺ (m/z)

MP=235° C. (decomposition).

EXAMPLE 648-fluoro-3-methyl-6-oxo-9-((S)-3-[1,2,3]triazol-1-yl-pyrrolidin-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (152)

Stage A: Preparation of 150

The product is prepared according the method described in US2003/0225107 by substituting 3(R)-azido-pyrrolidin-1-yl carbamic acidtert butyl ester for5(R)-azidomethyl-3-[4-(1-cyanocyclopropan-1-yl)-phenyl]oxazolidin-2-one(1.1 g, 5.2 mmol, 1.0 eq.). The raw product is subsequently used withoutany subsequent purification (550 mg, 44%).

Stage B: Preparation of 151

The method described for preparing 4c is used by substituting product150 (550 mg, 2.30 mmol, 1.0 eq.) for product 3c with 14 ml of HCl 4N indioxane. The raw product subsequently used without any subsequentpurification.

Stage C:8-fluoro-3-methyl-6-oxo-9-((S)-3-[1,2,3]triazol-1-yl-pyrrolidin-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

The method described in preparation 5c is used by substituting product151 (400 mg, 2.30 mmol, 4.0 eq.) for product 4c. The reaction medium isevaporated under reduced pressure. The result is triturated in methanoland then purified by preparative TLC. The expected product is obtainedas a yellow solid (30 mg, 33%).

HPLC (5%-95% ACN gradient in H₂O); >90%

MS (ESI⁺) (+0.1%, HCOOH): 401.4 [C₁₈H₁₇FN₆O₄+H]⁺ (m/z)

MP=235° C. (decomposition).

EXAMPLE 658-fluoro-3-methyl-9-[(R)-3-(3-methyl-isoxazol-5-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (155)

Stage A: Preparation of 153

The method described for preparing product 8a is used by substituting3-(S)-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g,5.34 mmol, 1.2 eq.) for 3-hydroxy-pyrrolidine-1-carboxylic acidtert-butyl ester, and 5-methyl-isoxazol-3-yl carbamic acid tert-butylester (880mg, 4.4mmol, 1.0 eq.) for product 7a. The raw product ispurified by chromatography on silica by eluting with a cyclohexane-ethylacetate mixture (1:0 to 8:2) and product 148 is obtained as a pale pinkoil (760 mg, 43%).

Stage B: Preparation of 154

The method described for preparing product 4a is used by substitutingproduct 153 (720 mg, 1.96 mmol, 1.0 eq.) for product 3a with 2 mL oftrifluoroacetic acid in 20 mL of dichloromethane. The residue ispurified by chromatography on silica by eluting with adichloromethane-NH₃ 7N mixture in methanol (0%-10% 7N NH₃ gradient inmethanol. The expected product is obtained as a brown oil (53 mg, 16%).

Stage C:8-fluoro-3-methyl-9-[(R)-3-(3-methyl-isoxazol-5-ylamino)-pyrrolidin-1-yl]-6-oxo-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

By using the method for preparing 5a, product 155 is obtained startingwith 50 mg of <<UBE-4>> (0.18 mmol, 1.0 eq.) and with product 154 (50mg, 0.30 mmol, 1.7 eq.) in 0.5 mL of anhydrous pyridine and 1 mL ofanhydrous acetonitrile in the presence of DABCO (50 mg, 0.45 mmol, 2.5eq.). The reaction medium is evaporated and the obtained solid istriturated in methanol and washed with methanol and then with ethylether. The expected product is obtained as a yellow solid (53 mg, 68%).

HPLC (5%-95% ACN gradient in H₂O); >95%

MS (ESI⁺) (+0.1%, HCOOH): 430.5 [C₂₀H₂₀FN₅O₅+H]⁺ (m/z)

MP=255-257° C.

EXAMPLE 668-fluoro-3-methyl-9-[(S)-3-(3-methyl-isoxazol-5-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (158)

Stage A: Preparation of 156

The method described for preparing 8a is used, by substituting3-(R)-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g,5.34 mmol, 1.2 eq.) for 3-hydroxy-pyrrolidine-1-carboxylic acidtert-butyl ester, and 5-methyl-isoxazol-3-yl carbarnic acid tert-butylester for product 7a (880 mg, 4.4 mmol, 1.0 eq.). The raw product ispurified by chromatography on silica by eluting with a cyclohexane-ethylacetate mixture (1:0 to 8:2) and product 151 is obtained as a colorlessoil (840 mg, 46%).

Stage B: Preparation of 157

The method described for preparing product 4a is used, by substitutingproduct 156 (800 mg, 2.18 mmol, 1.0 eq.) for product 3a with 2 mL oftrifluoroacetic acid in 20 mL of dichloromethane. The residue ispurified by chromatography on silica by eluting with a 7Ndichloromethane-NH₃ mixture in methanol (0%-10% 7N NH₃ gradient inmethanol). The expected product is obtained as a brown oil (178 mg,49%).

Stage C:8-fluoro-3-methyl-9-[(S)-3-(3-methyl-isoxazol-5-ylamino)-pyrrolidin-1-yl]-6-oxa-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

By using the method for preparing 5a, product 158 is obtained startingwith 150 mg of “UBE-4” (0.53 mmol, 1.0 eq.) and with product 157 (170mg, 1.02 mmol, 1.9 eq.) in 1 mL of anhydrous pyridine and 2 mL ofanhydrous acetonitrile in the presence of DABCO (150 mg, 1.34 mmol, 2.5eq.). The reaction medium is evaporated and the obtained solid istriturated in methanol and washed with methanol and then with ethylether. The expected product is obtained as a yellow solid (182 mg, 78%).

HPLC (5%-95% ACN gradient in H₂O); >95%

MS (ESI⁺) (+0.1%, HCOOH): 430.4 [C₂₀H₂₀FN₅O₅+H]⁺ (m/z)

MP=255-257° C.

EXAMPLE 678-fluoro-9-[(S)-3-(1H-imidazol-2-ylamino)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5carboxylicacid (163)

Stage A: Preparation of 159

To a solution of 2-amino-imidazole sulfate (10.0 g, 37.84 mmol, 1.0 eq.)in 100 mL of an aqueous (1N) sodium hydroxide solution, is added asolution of di-tert-butyl dicarbonate (16.5 g, 75.60 mmol, 2.0 eq.) in100 mL of dichloromethane. The mixture is stirred at room temperaturefor 16 hours. The organic phase is then isolated by decantation and thenwashed with water, dried and then concentrated under reduced pressure.The product obtained as a pink solid (11.2 g, quantitative) is usedwithout any subsequent purification.

Stage B: Preparation of 160

By using the method for preparing 7a, product 160 is obtained startingwith 159 (11.2 g, 37.84 mmol, 1.0 eq.). The raw expected product isobtained, which is purified by chromatography on silica by eluting witha cyclohexane-ethyl acetate mixture (10:0 to 4:6) and the expectedproduct 160 is obtained as a yellow solid (3.7 g, 35%).

Stage C: Preparation of 161

The method described for preparing 8a is used, by substituting3-(R)-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (545 mg,2.91 mmol, 1.5 eq.) for 3-hydroxy-pyrrolidine-1-carboxylic acidtert-butyl ester, and product 160 (550 mg, 1.94 mmol, 1.0 eq.) forproduct 7a. The raw product is purified by chromatography on silica byeluting with a cyclohexane-ethyl acetate mixture (1:0 to 7:3) andproduct 161 is obtained as a colorless oil (455 mg, 52%).

Stage D: Preparation of 162

The method described for preparing the product 4a is used, bysubstituting product 161 (450 mg, 0.99 mmol, 1.0 eq.) for product 3awith 0.8 mL of trifluoroacetic acid in 10 mL of dichloromethane. Themedium is co-evaporated with methanol and then triturated in ethylether. The expected product is obtained as a white powder (325 mg, 66%).

Stage E:8-fluoro-9-[(S)-3-(1H-imidazol-2-ylamino)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

By using the method for preparing 5a, product 163 is obtained, startingwith 100 mg of “UBE-4” (0.35 mmol, 1.0 eq.) and product 162 (305 mg,0.62 mmol, 1.8 eq.) in 1 mL of anhydrous pyridine and 2 mL of anhydrousacetonitrile in the presence of DABCO (80 mg, 0.71 mmol, 2.0 eq.). Thereaction medium is co-evaporated with ethanol. The obtained solid ispurified on an SCX column, and the obtained solid is then hot-trituratedin methanol and filtered. The expected product is obtained as a yellowsolid (24 mg, 16%).

HPLC (5%-95% ACN gradient in H₂O); >99%

MS (ESI⁺) (+0.1%, HCOOH): 415.48 [C₁₉H₁₉FN₆O₄+H]⁺ (m/z)

MP=245° C. (decomposition).

EXAMPLE 688-fluoro-9-[(R)-3-(1H-imidazol-2-ylamino)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

Stage A: Preparation of 164

The method described for preparing 8a is used, by substituting3-(S)-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (990 mg,5.29 mmol, 1.5 eq.) for 3-hydroxy-pyrrolidine-1-carboxylic tert-butylester and product 160 (1.0 g, 3.53 mmol, 1.0 eq.) for product 7a. Theraw product is purified by chromatography on silica by eluting with acyclohexane-ethyl acetate mixture (1:0 to 6:4) and the product 164 isobtained as a white foam (1.2 g, 75%).

Stage B: Preparation of 165

The method described for preparing 4a is used, by substituting product164 (675 mg, 1.49 mmol, 1.0 eq.) for product 3a with 1.2 mL oftrifluoroacetic acid in 15 mL of dichloromethane. The medium isco-evaporated with methanol and then triturated in ethyl ether. Theexpected product is obtained as a white powder (484 mg, 66%).

Stage C:8-fluoro-9-[R)-3-(1H-imidazol-2-ylamino)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

By using the method for preparing 5a, product 166 is obtained startingwith 140 mg of “UBE-4” (0.50 mmol, 1.0 eq.) and product 165 (460 mg,0.93 mmol, 1.9 eq.) in 1.5 mL of anhydrous pyridine and 3 mL ofanhydrous acetonitrile in the presence of DABCO (110 mg, 0.98 mmol, 2.0eq.). The reaction medium is co-evaporated with methanol. The obtainedresidue is purified on an SCX column and then on a Sephadex® LH-20column. The obtained solid is triturated in water, methanol and then inethyl ether. The expected product is obtained as a yellow solid (44 mg,21 %).

HPLC (5%-95% ACN gradient in H₂O); >95%

MS (ESI⁺) (+0.1%, HCOOH): 415.49 [C₁₉H₁₉FN₆O₄+H]⁺ (m/z)

MP=225° C. (decomposition).

EXAMPLE 698-fluoro-3-methyl-9-[(R)-3-(methyl-thiazol-2-yl-amino)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (170)

Stage A: Preparation of 167

By using the method for preparing 7a, product 167 is obtained startingwith 35b (500 mg, 1.26 mmol, 1.0 eq.). The raw product is subsequentlyused without any subsequent purification (350 mg, quantitative).

Stage B: Preparation of 168

To a solution of 167 (340 mg, 1.26 mmol, 1.0 eq.) in 8 mL of anhydrousDMF, is added sodium hydride (50 mg, 1.25 mmol, 1.0 eq.). The mixture isstirred at room temperature for 30 minutes, and then methyl iodide(0.118 mL, 1.89 mmol, 1.5 eq.) is added. The mixture is stirred at roomtemperature for 1 hour and then evaporated. The residue is dissolved inethyl acetate and then washed with water. The organic extracts are driedand then concentrated under reduced pressure. The raw product ispurified by chromatography on silica by eluting with a cyclohexane-ethylacetate mixture (1:0 to 6:4) and the product 164 is obtained as a yellowoil (270 mg, 75%).

Stage C: Preparation of 169

The method described for preparing the product 4a is used, bysubstituting product 168 for product 3a (265 mg, 0.93 mmol, 1.0 eq.)with 0.3 mL of trifluoroacetic acid in 5 mL of dichloromethane. Themedium is diluted with dichloromethane and water. The aqueous phase isalkalinized with an aqueous sodium hydroxide (1N) solution and extractedwith dichloromethane. The organic extracts are dried and concentratedunder reduced pressure. The expected product is obtained as a paleyellow oil (138 mg, 73%).

Stage D:8-fluoro-3-methyl-9-[(R)-3-(methyl-thiazol-2-yl-amino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid

By using the method for preparing 5a, product 170 is obtained, startingwith 100 mg of “UBE-4” (0.35 mmol, 1.0 eq.) and product 169 (130 mg,0.71 mmol, 2.0 eq.) in 0.5 mL of anhydrous pyridine and 1 mL ofanhydrous acetonitrile in the presence of DABCO (120 mg, 1.07 mmol, 3.0eq.). The reaction medium is co-evaporated with methanol. The obtainedsolid is triturated in methanol and in ethyl ether. The expected productis obtained as a yellow solid (137 mg, 88%).

HPLC (5%-95% ACN gradient in H₂O); >99%

MS (ESI⁺) (+0.1%, HCOOH): 446.5 [C₂₀H₂₀FN₅O₄+H]⁺ (m/z)

MP=222-224° C.

EXAMPLE 709-[(R)-3-(acetyl-thiazol-2-yl-amino)-pyrrolidin-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

A solution of product 36b (200 mg, 0.46 mmol, 1.0 eq.) intrifluoroacetic anhydride (5 mL) is heated to 90° C. for 6 hours. Thereaction medium is cooled down to room temperature, the mixture isfiltered and the filtrate is concentrated under reduced pressure. Theobtained residue is re-crystallized from methanol and then purified bypreparative HPLC (acetonitrile/H₂O gradient). The expected product isobtained as a beige solid (25 mg, 88%).

HPLC (5%-95% ACN gradient in H₂O); >95%

MP=220-222° C.

EXAMPLE 718-fluoro-3-methyl-9-[3-amino-4-(thiazol-2-ylamino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (177)

Stage A: preparation of 171

A solution of triethyl phosphonoacetate (2.6 g, 11.60 mmol, 1.3 eq.) inTHF (5 mL) is added dropwise to a suspension of NaH (424 mg, 10.60 mmol,1.2 eq.) in THF (8 mL) at 0° C. The reaction medium is stirred at 0° C.for 30 minutes and a solution of 2-formylthiazole (1.0 g, 8.84 mmol, 1.0eq.) in THF (8 mL) is added. The mixture is stirred at room temperaturefor 16 hours. The reaction medium is concentrated and then diluted withdichloromethane and washed with water and a saturated sodium chloridesolution. The isolated organics extracts are dried and then the solventis evaporated under reduced pressure. The raw expected product isobtained, which is purified by chromatography on silica by eluting witha cyclohexane-ethyl acetate mixture (10:0 to 85:15) and the expectedproduct 171 is obtained as a colorless oil (1.7 g, 100%).

Stage B: Preparation of 172

N-methoxymethyl)-N-(trimethylsilylmethyl)-benzyl-amine (466 mg, 1.96mmol, 1.2 eq.) and a trifluoroacetic acid solution in dichloromethane(1N, 170 μL, 0.17 mmol, 0.1 eq.) are added to a solution of 171 (300 mg,1.64 mmol, 1.0 eq.) in dichloromethane (5 mL) at 0° C. The reactionmedium is stirred at 0° C. for 20 minutes and at room temperature for 4hours. The medium is then diluted with dichloromethane, washed withwater and then with an aqueous saturated sodium chloride solution. Theisolated organic extracts are dried and the solvent is evaporated underreduced pressure. The pure expected product is obtained as a yellow oil(516 mg, 98%).

Stage C: Preparation of 173

A solution of 172 (500 mg, 1.73 mmol, 1.0 eq.) in an aqueous 6N HClsolution is stirred at room temperature for 16 hours. The reactionmedium is then evaporated under reduced pressure, co-evaporated withtoluene, and then dried on P₂O₅ in vacuo. The expected product isobtained pure as a white solid (497 mg, 99%).

Stage D: Preparation of 174

To a suspension of 173 (2.3 g, 8.03 mmol, 1.0 eq.) in tert-butyl alcohol(30 mL), are added triethylamine (2.30 mL, 10.41 mmol, 1.3 eq.) anddiphenylphosphoryl azide (2.30 mL, 16.55 mmol, 2.0 eq.). The reactionmedium is stirred at 90° C. for 16 hours. Triethylamine (2.30 mL, 16.55mmol, 2.0 eq.) and di-tert-butyl dicarbonate (2.6 g, 11.91 mmol, 1.5eq.) are added to the mixture and the latter is stirred at 55° C. for 3hours. The reaction medium is concentrated under reduced pressure. Theraw product is purified by chromatography on silica by eluting with acyclohexane-ethyl acetate mixture (1:0 to 4:6) and the product 174 isobtained as a beige solid (296 mg, 10%).

Stage E: Preparation of 175

To a solution of 174 (296 mg, 0.82 mmol, 1.0 eq.) in chloroform (4 mL),is added chlorobenzyl formate (281 mg, 1.64 mmol, 2.0 eq.). The reactionmedium is stirred at 60° C. for 7 hours. The reaction medium isconcentrated under reduced pressure. The raw product is purified bychromatography on silica by eluting with a cyclohexane-ethyl acetatemixture (1:0 to 4:6) and the product 175 is obtained as a beige foam(220 mg, 67%).

Stage F: Preparation of 176

To a solution of 175 (250 mg, 0.62 mmol, 1.0 eq.) in acetonitrile (4.5mL), are added sodium iodide (371 mg, 2.47 mmol, 4.0 eq.) andtrimethylsilyl chloride (269 mg, 2.47 mmol, 2.0 eq.). The reactionmedium is stirred at room temperature for 1 hour and methanol is thenadded (5 mL). The reaction medium is concentrated under reducedpressure. The raw product is purified on a Sephadex® LH-20 column andthen on an SCX column. The product 176 is obtained as a colorless oil(62 mg, 59%).

Stage G:8-fluoro-3-methyl-9-[3-amino-4-(thiazol-2-yl-amino)-pyrrolidin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

By using the method for preparing 5a, product 177 is obtained startingwith 52 mg of “UBE-4” (0.18 mmol, 1.0 eq.) and with product 176 (62 mg,0.36 mmol, 2.0 eq.) in 0.5 mL of anhydrous pyridine and 1 mL ofanhydrous acetonitrile in the presence of DABCO (101 mg, 0.91 mmol, 2.5eq.). The reaction medium is co-evaporated with methanol. The obtainedsolid is triturated in methanol and purified by preparative TLC. Theexpected product is obtained as a yellow solid (19 mg, 22%).

HPLC (5%-95% ACN gradient in H₂O); >99%

MS (ESI⁺) (+0.1%, HCOOH): 432.4 [C₁₉H₁₈FN₅O₄S+H]⁺ (m/z)

MP=240-245° C.

EXAMPLE 728-fluoro-9-[(R)-3-H-imidazol-2-ylamino)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (182)

Stage A: Preparation of 178

The product is prepared according to the method described in US2003/0225107 by substituting 3-hydroxy-pyrrolidinol with3-(S)-hydroxy-pyrrolidinol (1.0 g, 5.34 mmol, 1.0 eq.). 178 is obtainedas an orange oil (1.2 g, 100%).

Stage B: Preparation of 179

To a solution of product 178 (907 mg, 4.27 mmol, 1.0 eq.) in 25 mL ofmethanol, palladium on charcoal (454 mg, 0.43 mmol, 0.1 eq.) is added.The reaction medium is submitted to hydrogenation at atmosphericpressure and at room temperature for 6 hours. The reaction medium isthen filtered on celite and concentrated under dry conditions underreduced pressure. The expected compound is obtained as a yellow oil (740mg, 93%).

Stage C: Preparation of 180

The method described in the preparation of 3a-3b is used by substituting3-(R)-amino-pyrrolidine-1-carboxylic acid tert-butyl ester 179 for3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester. Theexpected compound is obtained as a yellow solid (482 mg, 55%).

Stage D: Preparation of 181

The method described in the preparation of 4c is used, by substitutingproduct 180 for product 3c. The expected compound is obtained as ayellow solid (368 mg, 100%).

Stage E:8-fluoro-9-[(R)-3-(1H-imidazol-2-ylamino)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

The method described in the preparation of 5c is used, by substitutingproduct 181 (367 mg, 1.8 mmol, 1.8 eq.) for product 4c, the expectedcompound is obtained as a yellow solid (23 mg, 6%).

HPLC (5%-80% ACN gradient in H₂O); >95%

MS (ESI⁺) (+0.1%, HCOOH): 427.2 [C₂₀H₁₉FN₆O₄+H]⁺ (m/z)

MP=255° C. (decomposition).

EXAMPLE 738fluoro-9-[(R)-3-(1H-imidazol-2-ylamino)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (187)

Stage A: Preparation of 183

The product is prepared according to the method described in US2003/0225107 by substituting 3-hydroxy-pyrrolidinol with3-(R)-hydroxy-pyrrolidinol (2.0 g, 10.68 mmol, 1.0 eq.). 183 is obtainedas a yellow liquid (2;0 g, 89%).

Stage B: Preparation of 184

To a solution of product 178 (2.0 g, 9.42 mmol, 1.0 eq.) in 40 mL ofmethanol, palladium on charcoal (1.0 g, 0.94 mmol, 0.1 eq.) is added.The reaction medium is submitted to hydrogenation at atmosphericpressure and at room temperature for 6 hours. The reaction medium isthen filtered on celite and concentrated under dry conditions underreduced pressure. The expected compound is obtained as a yellow oil (1.7g, 97%).

Stage C: Preparation of 185

The method described in the preparation of 3a-3b is used by substituting3-(S)-amino-pyrrolidin-1-carboxylic acid tert-butyl ester 184 for3-aminomethyl-pyrrolidin-1-carboxylic acid tert-butyl ester. Theexpected compound is obtained as a yellow solid (510 mg, 26%).

Stage D: Preparation of 186

The method described in the preparation of 4c is used by substitutingproduct 185 for product 3c. The expected compound is obtained as ayellow solid (470 mg, 100%).

Stage E:8-fluoro-9-[(S)-3-(1H-imidazol-2-ylamino)-pyrrolidin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid

By using the method for preparing 5a, product 187 is obtained startingwith 100 mL of “UBE-4” (0.35 mmol, 1.0 eq.) and with product 186 (150mg, 0.91mmol, 2.6 eq.) in 0.5 mL of anhydrous pyridine and 1.5 mL ofanhydrous acetonitrile in the presence of DABCO (100 mg, 0.89 mmol, 2.5eq.). The obtained precipitate is filtered and then washed withacetonitrile and ethyl ether. The expected product is obtained as ayellow solid (120 mg, 80%).

HPLC (5%-95% ACN gradient in H₂O); >99%

MS (ESI⁺) (+0.1%, HCOOH): 432.4 [C₂₀H₁₉FN₆O₄+H]⁺ (m/z) MP=257-259° C.

EXAMPLE 748-fluoro-3-(2-fluoro-ethyl)-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid (196)

Stage A: Preparation of 188

A solution of N-butyllithium (2.5M/hexane, 8.3 mL, 20.68 mmol, 4.4 eq.)is added to a solution of monoethyl malonate (1.36 g, 10.35 mmol, 2.2eq.) in THF (15 mL) at 0° C. The reaction medium is cooled to −50° C.and a solution of 2,3,4,5-tetrafluorobenzoyl chloride in THF (5 mL) isadded dropwise. The mixture is then stirred at room temperature for 16hours. The reaction is hydrolyzed by an aqueous 1N HCl solution, andthen the organic phase is extracted with ethyl acetate. The isolatedorganic extracts are dried and the solvent is then evaporated underreduced pressure. The raw expected product is obtained, which ispurified by chromatography on silica by eluting with a cyclohexane-ethylacetate mixture (1:0 to 9:1) and the expected product 188 is obtained asa pale orange oil (600 mg, 50%).

Stage B: Preparation of 189

A mixture of product 188 (1.8 g, 6.70 mmol, 1.0 eq.), triethylorthoformate (1.7 mL, 10.05 mmol, 1.5 eq.) and acetic anhydride (2.7 mL,26.80 mmol, 4.0 eq.) is stirred at 125° C. in a sealed tube for 16hours. The medium is concentrated under reduced pressure and the product189 (1.8 g, 88%) is used without any subsequent purification.

Stage C: Preparation of 190

A solution of Boc-hydrazine (870 mg, 6.55 mmol, 1.1 eq.) and of product189 (1.8 g, 5.95 mmol, 1.0 eq.) in toluene (9 mL) is stirred at 80° C.for 4 hours. The reaction is hydrolyzed by adding water, and the organicphase is then extracted with ethyl acetate. The isolated organicextracts are dried and the solvent is then evaporated under reducedpressure. The raw expected product is obtained, which is purified bychromatography on silica by eluting with a cyclohexane-ethyl acetatemixture (1:0 to 5:5) and the expected product 190 is obtained as a paleyellow solid (800 mg, 35%).

Stage D: Preparation of 191

To a solution of product 190 (600 mg, 1.55 mmol, 1.0 eq.) and oftriphenyl phosphine (615 mg, 2.30 mmol, 1.5 eq.) in THF (6 mL) at 0° C.,are added diethyl azodicarboxylate (1.08 mL, 2.30 mmol, 1.5 eq.) and2-fluoroethanol. The reaction medium is stirred at room temperature for16 hours. The reaction is hydrolyzed by adding water, and the organicphase is then extracted with ethyl acetate and washed with an aqueous 1NHCl solution. The isolated organic extracts are dried and the solvent isthen evaporated under reduced pressure. The raw expected product isobtained, which is purified by chromatography on silica by eluting witha cyclohexane-ethyl acetate mixture (1:0 to 5:5) and the expectedproduct 191 is obtained as a yellow solid (495 mg, 73%).

Stage E: Preparation of 192

The method described for preparing the product 4a is used, bysubstituting for product 3a, product 191 (514 mg, 1.19 mmol, 1.0 eq.)with 2.5 mL of trifluoroacetic acid in 5 mL of dichloromethane. Themedium is diluted with dichloromethane and water. The aqueous phase isalkalinized with an aqueous (1N) sodium hydroxide solution and extractedwith dichloromethane. The organic extracts are dried and concentratedunder reduced pressure. The expected product is obtained as a paleyellow oil (315 mg, 79%).

Stage F: Preparation of 193

A suspension of product 192 (310 mg, 1.19 mmol, 1.0 eq.) and ofparaformaldehyde (1.2 g, 39.90 mmol, 40.0 eq.) in water is stirred at110° C. in a sealed tube for 48 hours. The medium is cooled at roomtemperature and the obtained precipitate is filtered, washed withmethanol, and ethyl ether. The expected product is obtained as a whitesolid (254 mg, 77%).

Stage G: Preparation of 194

A suspension of product 194 (600 mg, 1.66 mmol, 1.0 eq.) in THF (35 mL)is heated to reflux in less than 5 minutes and TBAF (3.7 mL, 3.67 mmol,2.2 eq.) is added very rapidly. The reaction medium is stirred at refluxfor 20 minutes. The mixture is then poured onto a saturated sodiumcarbonate solution, and the organic phase is then separated and thenextracted with ethyl acetate. The isolated organic extracts are driedand the solvent is then evaporated under reduced pressure. The residueis taken up in ethyl acetate and a precipitate is formed by adding ethylether. The precipitate is filtered and dried in vacuo. The expectedproduct is obtained as a beige solid (240 mg, 42%).

Stage H: Preparation of 195

Lithium hydroxide (227 mg, 5.40 mmol, 5.0 eq.) is added to a solution ofproduct 195 (370 mg, 1.08 mmol, 1.0 eq.) in a water/THF mixture (4mL/4mL). The reaction medium is stirred at room temperature for 7 hours.The formed precipitate is filtered, washed with ethyl ether and thendried in vacuo. The expected product is obtained as a white solid (286mg, 84%).

Stage I:8-fluoro-3-(2-fluoro-ethyl)-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid

By using the method for preparing 5a, product 196 is obtained startingwith 100 mg of product 195 (0.32 mmol, 1.0 eq.) and with product 35b(108 mg, 0.64 mmol, 2.0 eq.) in 0.8 mL of anhydrous pyridine and 1.5 mLof anhydrous acetonitrile in the presence of DABCO (72 mg, 0.64 mmol,2.0 eq.). The reaction medium is evaporated under reduced pressure. Theresult is triturated in methanol and then purified by preparative TLC.The expected product is obtained as a yellow solid (18 mg, 12%).

HPLC (5%-95% ACN gradient in H₂O); >99%

MS (ESI⁺) (+0.1%, HCOOH): 432.4 [C₂₀H₁₉F₂N₅O₄S+H]⁺ (m/z)

MP=242-245° C.

Anti-Infectious Activity Test Protocol

a. Aim of the study and choice of strains

In order to assess the anti-infectious activity, a test to determine theminimal inhibitory concentrations (MIC), of the synthesized molecules isimplemented. This comparative test, using a reference fluoroquinolone,measures the minimum inhibitory concentrations for the principalreference and in-situ bacteria, isolated from human and animalpathologies (canine, feline, bovine or porcine). These bacteriarepresent different resistance populations vis-a-vis thefluoroquinolones for each bacterial species selected and come fromVetoquinol S.A.'s private collection or ATCC references, M. haemolytica(2); B. bronchiseptica; P. aeruginosa (2); E. coli (3); S. aureus (3);S. uberis; M. bovis and bovirhinis; C. perfringens.

b. Experimental Methodology for Determining MICs

MIC determination is carried out by microdilution in a liquid medium.The method used for the aerobic and anaerobic bacteria is based on theCLSI (NCCLS) M31-A (May 2002) guideline “Performance Standards forAntimicrobial Disk and dilution susceptibility tests for bacteriaisolated from animals”. The method used for the mycoplasma is based onthe CLSI (NCCLS) M3 1-A (May 2002) guideline and the article by F.Poumarat and J. L. Martel. For each molecule, the concentrations to betested vis-a-vis the strains are:

either between 0.001 and 1 μg/ml

or between 0.03 and 32 μg/ml

Controls were introduced into each test.Acceptable results of these controls validate the results obtained foreach molecule.

c. Results

The results obtained for each of the molecules are summarized in tableform in order to:

Assess the intrinsic performance of the molecule

Facilitate comparison between molecules

Discuss the data obtained in relation to the reference.

TABLE OF MICs (μg/ml) Compound Bor of example Man hae s Man hae r bronPse aer s Pse aer r E coli Str ube  8 0.25 32 >1 8 >32 0.5 0.25  1 0.0616 0.5 8 16 0.25 <0.03  7 0.06 16 0.5 2 16 0.25 0.06 19 0.03 8 0.12 2 80.06 <0.03 18 0.12 >32 0.25 4 32 0.5 0.25 10 0.03 >32 2 4 >32 0.25 <0.0333 0.06 8 0.5 0.5 8 0.06 0.12 27 0.008 4 2 0.06 2 0.03 0.25 29 0.03 8 >10.25 4 0.06 0.5 28 0.008 4 1 0.06 1 0.03 0.25 38 0.03 16 1 4 32 0.12<0.03 34 0.03 8 0.5 0.5 8 0.03 0.12 35 0.06 8 1 0.5 8 0.06 0.12 39 0.0316 0.5 2 16 0.25 0.12 E. coli E. fae-calis Compound Myc Clo ATCC ATCC ofexample Sta aur s Sta aur r bov per 25922 29212 M. bovirhinis  8 0.06 40.06 <0.03 0.12 0.25 0.06  1 <0.03 0.5 <0.03 0.06 0.12 ≦0.03 0.06  7<0.03 0.5 <0.03 0.06 0.25 ≦0.03 0.06 19 <0.03 0.25 <0.03 <0.03 0.25 0.060.25 18 <0.03 4 0.25 0.06 0.06 ≦0.03 ≦0.03 10 <0.03 4 0.12 <0.03 1 0.252 33 <0.03 2 0.5 0.06 0.03 0.25 27 0.12 8 1 0.25 0.03 2 1 29 0.12 8 0.50.25 0.06 1 to 2 1 28 0.12 4 1 0.12 0.03 1 to 2 38 0.06 2 0.12 <0.030.12 0.06 0.25 34 <0.03 2 0.5 <0.03 0.03 0.25 to 0.5  0.12 35 0.06 2 0.50.12 0.03 0.25 39 <=0.03 2 0.12 <=0.03 0.03 to 0.12 0.12 0.06 Names ofthe bacteria: Man hae = Mannheimia haemolytica, Bor bron = Bordetellabronchiseptica, Pse aer = Pseudomonas aeruginosa, s = susceptible E.coli = Escherichia coli, Str ube = Streptococcus uberis, Sta aur =Staphylococcus aureus, Myc bov = Mycoplasma bovis, Clo per = Clostridiumperfringens r = resistant

1. A compound of formula (I) comprising:

in which either R₁ represents: H, OH, NH₂, —(CH₂)_(m)—NR_(a)R_(b) inwhich m=0. 1 or 2, R_(a) and R_(b) are identical or different andrepresent H, linear, branched or cyclic (C₁-C₆) alkyl, (C₃-C₆)cycloalkyl-(C₁-C₆)-alkyl; or also represent R_(c), S(O)₂R_(c),C(O)R_(c), S(O)₂R_(d) or C(O)R_(d); or R_(a) and R_(b) form togetherwith the nitrogen atom, an R_(c) radical; R_(c) represents a saturated,unsaturated or aromatic 5- to 6-member ring containing 1 to 4heteroatoms chosen from N, O and S, optionally substituted by 1 to 3(C₁-C₆) alkyl radicals, said ring being linked, if appropriate, to thenitrogen atom of NR_(a)R_(b) by a nitrogen atom or a carbon atom; R_(d)represents a linear or branched (C₁-C₆) alkyl or (C₃-C₆) cyclic alkylradical, optionally substituted by 1 to 4 halogens; or R₁ representsR_(c) or CHR_(e)R_(c) or CHR_(e)R_(d); R_(c) and R_(d) are as definedabove, R_(e) represents H, OH, NH₂, NH—(C₁-C₆)-alk or N—(C₁-C₆)-alk₂, orNH—(C₁-C₇)-acyl or NHR_(c), R_(c) being as defined above; R₂ represents:H, (CH₂)_(m)—NR_(a)R_(b), R_(c), CHR_(e)R_(c) or CHR_(e)R_(d), R_(a),R_(b), R_(c), R_(d) and R_(e) are as defined above; and R′₂ representsH; it being understood that R₁ and R₂ cannot at the same time be H orthat R₁ and R₂ or R₂ and R₁ cannot be one (CH₂)_(m)—NR_(a)R_(b) or R_(c)or H and the other one OH, or one H and the other one NH₂, or one H andthe other one (CH₂)_(m)—NR_(a)R_(b) in which R_(a) and R_(b) represent Hor (C₁-C₆) alkyl or C(O)R_(d), in which R_(d) represents anunsubstituted linear or branched (C₁-C₆) alkyl or (C₃-C₆) cyclic alkylradical; or R₁ has the above definition except H and R₂ and R′₂ togetherrepresent gem (C₁-C₆) dialkyl or (C₁-C₆) alkyl-oxime, or R₂ and R′₂represent respectively R_(c) or R_(d) and OH, NH₂, NHR_(c) or NHR_(f),R_(c) and R_(d) being as defined above and R_(f) being a (C₁-C₇) acylradical; or R₁ represents H and R₂ and R′₂ together represent (C₁-C₆)alkyl-oxime or one represents R_(c) and the other one represents OH,NH₂, NHR_(c) or NHR_(f), R_(c) and R_(f) being defined as above; n is 0or 1; R₃ and R′₃, identical or different, represent H or (C₃-C₆) alkyloptionally substituted by 1 to 3 halogens or R₃ represents a (C₁-C₆)alkoxy carbonyl group and R′₃ represents H; R₄ represents methyloptionally substituted by one to three halogens; R₅ represents H,(C₃-C₆) alkyl or (C₇-C₁₂) arylalkyl; R₆ represents H, fluorine, NO₂, CF₃or CN; in the form of mixtures of enantiomers or single enantiomers, aswell as their addition salts with mineral and organic acids and theirsalts with mineral or organic bases.
 2. A compound of formula (I)according to claim 1, in which R₃ and R′₃ represent H and R₄ representsmethyl.
 3. A compound of formula (I) according to claim 1, in which R₆represents fluorine.
 4. A compound of formula (I) according to claim 1,in which one of the substituents R₁ or R₂ represents(CH₂)_(m)—NR_(a)R_(b) in which m is 0 or 1, Rc, CHR_(e)R_(c) orCHR_(e)R_(d) and the other represents H.
 5. A compound of formula (I)according to claim 1, in which one of the substituents R₁ or R₂represents (CH₂)_(m)—NR_(a)R_(b) in which m is 0 and the otherrepresents H.
 6. A compound of formula (I) according to claim 5, inwhich m=0, one of the substituents R_(a) or R_(b) represents a 5- or6-member aromatic ring, containing 1 to 4 heteroatoms chosen from N, Oand S, optionally substituted by 1 to 3 (C₁-C₆) alkyl radicals, saidring being linked, if appropriate, to the nitrogen atom of NR_(a)R_(b)by a nitrogen atom or a carbon atom, and the other represents H.
 7. Acompound of formula (I) according to claim 5, in which m=0, one of thesubstituents R_(a) or R_(b) represents a C(O)Rd radical and the otherrepresents H.
 8. A compound of formula (I) according to claim 1, inwhich one of the substituents R₁ or R₂ represents CHR_(e)R_(c) orCHR_(e)R_(d) and the other represents H.
 9. A compound of formula (I)according to claim 1, in which R₁ represents OH or NH₂ and R₂ and R′₂represent gem (C₁-C₆) dialkyl.
 10. A compound of formula (I) accordingto claim 1, in which R₁ represents hydrogen or —(CH₂)m—NR_(a)R_(b) andR₂ and R′₂ represent (C₁-C₆) alkyl oxime.
 11. A compound of formula (I)according to claim 1, in which n is
 0. 12. A compound according to claim1, selected from the group consisting of:8-fluoro-3-methyl-6-oxo-9-(3-(pyrazine-2-ylaminomethyl)-pyrrolidine-1-yl(-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,8-fluoro-3-methyl-6-oxo-9-(3-pyrazine-2-ylamino)-pyrrolidine-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,8-fluoro-3-methyl-6-oxo-9-(3-((1,3,4(thiadiazol-2-ylamino)-pyrrolidine-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,8-fluoro-3-methyl-6-oxo-9-[(S)-3-(thiazol-2-ylamino)-pyrrolidine-1-yl]-(-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,8-fluoro-3methyl-6-oxo-9-(3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,8-fluoro-3-methyl-6-oxo-9-((R)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl(-2,3-dihydro-6H-1-oxa-3.3a-diaza-phenalene-5-carboxylicacid,9-((R,S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,9-((R)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,9-(3-(amino-thiazol-2-yl-methyl)-pyrrolidine-1-yl(-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,8-fluoro-9-(3-((Z/E)-methoxyimino(-pyrrolidine-1-yl(-3-methyl-6-oxo-2,3-dihydro-6-H-1H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,8-fluoro-9-(3-(aminomethyl)-4-methoxyimino-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,8-fluoro-3-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,8-fluoro-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid,9-((S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid, and salts thereof.
 13. A compound selected from the groupconsisting of:8-Fluoro-3-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid;8-fluoro-3methyl-6-oxo-9-(3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid;8-Fluoro-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid;9-((R,S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid;9-((S)-4-Amino-3,3-dimethyl-pyrrolidin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid; and salts thereof.
 14. A compound according to claim 13, which is:8-Fluoro-3-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid;8-Fluoro-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid; or9-((S)-4-Amino-3,3-dimethyl-pyrrolidin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylicacid.
 15. A method for the preparation of a compound of claim 1, whereina compound of formula (II) is treated:

in which R₃, R′₃, R₄ and R₆ are as defined in claim 1 and R′₅ has thevalues of R₅ defined above or represents another group protecting thecarboxy function, by a compound of formula (III):

in which R₁, R₂, R′₂ and n are defined as in claim 1, in the presence ofa base, then, if appropriate, the protective group/s present areeliminated and, if appropriate, esterified by action of an alcohol or ofa suitable and salified derivative.
 16. A method for the preparation ofa compound of claim 1, in which R₂ and R′₂ represent (C₁-C₆)alkyl-oxime, wherein a compound of formula (IV) is treated:

by an alkoxylamine or a salt thereof.
 17. A pharmaceutical compositioncomprising a compound according to claim
 1. 18. A pharmaceuticalcomposition comprising a compound according to claim
 11. 19. Apharmaceutical composition comprising a compound according to claim 12.20. A pharmaceutical composition comprising a compound according toclaim
 13. 21. A method of treating a bacterial infection comprisingadministering to a mammal in need thereof an antibacterially effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof with an acid or a base.
 22. A method of treating a bacterialinfection according to claim 21, comprising administering to an animalin need thereof an antibacterially effective amount of a veterinarymedicine comprising a compound of claim
 1. 23. A method of treating abacterial infection comprising administering to a mammal in need thereofan antibacterially effective amount of a compound of claim 12 or apharmaceutically acceptable salt thereof with an acid or a base.
 24. Amethod of treating a bacterial infection comprising administering to amammal in need thereof an antibacterially effective amount of a compoundof claim 13 or a pharmaceutically acceptable salt thereof with an acidor a base.
 25. A method of treating a bacterial infection according toclaim 24, comprising administering to an animal in need thereof anantibacterially effective amount of a veterinary medicine comprising acompound of claim 1.